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Molecular Signatures Associated with Treatment of Triple-Negative MDA-MB231 Breast Cancer Cells with Histone Deacetylase Inhibitors JAHA and SAHA
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Molecular Signatures Associated with Treatment of Triple-Negative MDA-MB231 Breast Cancer Cells with Histone Deacetylase Inhibitors JAHA and SAHA
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† Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy
‡ Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
§ Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, United Kingdom
*E-mail: [email protected]. Phone: +3909123897331.
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Chemical Research in Toxicology

Cite this: Chem. Res. Toxicol. 2017, 30, 12, 2187–2196
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https://doi.org/10.1021/acs.chemrestox.7b00269
Published November 12, 2017

Copyright © 2017 American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

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Jay Amin hydroxamic acid (JAHA; N8-ferrocenylN1-hydroxy-octanediamide) is a ferrocene-containing analogue of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA). JAHA’s cytotoxic activity on MDA-MB231 triple negative breast cancer (TNBC) cells at 72 h has been previously demonstrated with an IC50 of 8.45 μM. JAHA’s lethal effect was found linked to perturbations of cell cycle, mitochondrial activity, signal transduction, and autophagy mechanisms. To glean novel insights on how MDA-MB231 breast cancer cells respond to the cytotoxic effect induced by JAHA, and to compare the biological effect with the related compound SAHA, we have employed a combination of differential display-PCR, proteome analysis, and COMET assay techniques and shown some differences in the molecular signature profiles induced by exposure to either HDACis. In particular, in contrast to the more numerous and diversified changes induced by SAHA, JAHA has shown a more selective impact on expression of molecular signatures involved in antioxidant activity and DNA repair. Besides expanding the biological knowledge of the effect exerted by the modifications in compound structures on cell phenotype, the molecular elements put in evidence in our study may provide promising targets for therapeutic interventions on TNBCs.

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Introduction

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Histone deacetylase inhibitors (HDACis) are chemically heterogeneous promising anticancer agents that restore a relaxed, hyperacetylated chromatin structure and potentially lead to re-expression of silenced genes or silencing of downstream genes, ultimately inducing death, apoptosis, and cell cycle arrest in cancer cells also via non histone-targeted mechanisms such as perturbations of p53, cytokine signaling pathways, and angiogenesis (e.g., ref 1). HDACis are grouped into different categories on the basis of their chemical nature, and the consequence of this molecular diversity is that the precise mechanism through which these compounds work is still poorly understood.
Suberoylanilide hydroxamic acid (SAHA), that is, Vorinostat, is a prototypical HDACi targeting class I and II HDAC approved in 2006 by the Food and Drug Administration for treatment of cutaneous T-cell lymphoma. (2) A number of studies have focused on the understanding of the biological properties of the compound as an anticancer agent, especially against tumors with intrinsic highly malignant potential. Triple-negative breast cancer (TNBC) is a tumor histotype, which is poorly responsive to hormonal therapies and to HER2-targeting drugs and usually associated with worse prognosis than other breast cancers. It is therefore very important to develop and test novel drugs or analogues of pre-existing drugs that counteract TNBC cell growth. In this context, drugs targeting multiple signaling pathways and epigenetic drugs appear to be the most promising. (3) Exposure of TNBC MDA-MB231 cells to SAHA was found to determine the modification of selected gene expression patterns, the disruption of transduction signaling, and the onset of apoptosis. (4-7)
Several manipulations of the core structure of SAHA have been carried out to probe the effect of such SAR (structure activity relationships) modifications on both HDAC inhibitory activity and cytotoxic effects on cancer cells (e.g., ref 8). HDACis typically contain a cap (often aryl group), a linker, and a zinc-binding group. Spencer et al. (9) reported the synthesis of metal-based SAHA analogues that contain a ferrocene cap that are air stable and readily modifiable synthetically such as Jay Amin hydroxamic acid (JAHA). If compared with parental SAHA, JAHA displays similar broad inhibitory profiles toward class I HDACs, including HDAC8, whereas it is inactive on class IIa HDACs. Indeed, many studies have shown that the introduction of a ferrocene motif can lead to significant changes in bioactivity not only due to its size and shape, which may alter interactions with crucial residues in active sites for example, but also due to its potential for redox activity (Fe(II)/Fe(III) and induction of reactive oxygen species. (10-14)
Given its different structure, this new compound underwent further study, and in a previous set of experimental assays its ability to counteract TNBC MDA-MB231 cell growth and the related biological aspects were tested. JAHA exhibited a remarkable activity on cell viability and proliferation with an IC50 of 8.45 μM at 72 h. In particular, JAHA’s cytotoxic activity implied (i) cell cycle perturbation, likely related to an inability of cells to proceed through the G2/M transition, (ii) an early increase of reactive oxygen species production followed by dissipation of mitochondrial transmembrane potential, and (iii) the inhibition of the autophagic process that plays a pro-survival role in this cell line. Noteworthy, JAHA did not induce the onset of apoptosis that was instead promoted by the archetypal SAHA at the same concentration. (4) Contrary to JAHA, SAHA was proven to enhance the autophagic process in different model systems (e.g., ref 15). Moreover, dealing with survival-related signal transduction pathways, Librizzi et al. (16) reported that, differently from SAHA, JAHA induced the deactivation of pERK1/2, leaving pAKT levels unaltered in MDA-MB231 cells. The resulting inhibition of DNMT1 and DNMT3b methyltransferase activity resulted in a generalized DNA demethylation following JAHA treatment with consequent implications in transcriptional regulation and gene expression pattern.
These cumulative results highlighted a modification of the biological effect consequent to the manipulation of the original molecular structure. It is widely acknowledged that the characterization of the biological activity of new potential anticancer compounds, such as ferrocene-based SAHA analogues, is necessary to establish drug safety and efficacy profiles. In addition, information on the mode of action of the different HDACis may reveal new molecular targets of putative applicative interest, which ultimately may be useful in the design of more appropriate intervention and therapies for tumors with inherent aggressive biology and limited treatment options such as TNBCs. To get novel insight on how MDA-MB231 breast cancer cells respond to the cytotoxic effect induced by JAHA, and to compare the biological effect of the related compounds JAHA and SAHA, we have employed a combination of differential display-PCR, proteome analysis, and Comet assay techniques and shown different molecular signature profiles induced by exposition to either HDACis. As well as expanding the biological knowledge of the effect exerted by the modifications in compound structures on cell phenotype, the molecular elements put in evidence in our study may provide promising targets for therapeutic interventions on TNBCs.

Experimental Procedures

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Cells and Treatments

MDA-MB231 breast tumor cells were maintained in RPMI 1640 medium plus 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin, and 2.5 mg/L amphotericin B (Invitrogen, Carlsbad, CA, USA), at 37 °C in a 5% CO2 atmosphere. The cells were detached from flasks with 0.05% trypsin-EDTA, counted, and plated at the necessary density for treatment after achieving 60–80% confluency. The HDACis SAHA and JAHA, the latter synthesized as reported in Spencer at al., (9) were dissolved in dimethyl sulfoxide as stock solutions. Cells (1 × 106) were plated in 75 cm2 flasks and allowed to adhere overnight. Then the cells were treated with either JAHA or SAHA at 8.45 μM concentration or with the vehicle for 18, 24, and 48 h.

Messenger RNA Isolation and Reverse Transcription

Isolation of total RNA from monolayers of trypsinized control and HDACi-exposed cells and reverse transcriptase reaction were performed with TRIzol reagent (Invitrogen) as described by Sirchia and Luparello. (17) Messenger RNA-enriched samples from total RNA preparations were obtained using Terminator 5′-phosphate-dependent exonuclease (Epicenter, Madison, WI, USA) following manufacturer’s instructions, and the mRNA preparations were purified from excess EDTA, tRNA, 5S rRNA, and other small RNA species by LiCl precipitation. The cDNAs were synthesized from 250 ng of mRNA in the presence of random hexamer primers using Superscript II reverse transcriptase (Invitrogen), and their quality was checked by amplification of “housekeeping” β-actin cDNA.

Differential Display (DD) and Real Time-PCR

For differential expression analysis, DD-PCR experiments were performed as already reported (e.g., refs 18 and 19) using 25 pmol of the arbitrary 10-mer primers designed by Sokolov and Prokop, (20) in combinations of two, and 3.6 U of AmpliTaq DNA polymerase, Stoffel fragment (Applied Biosystems/Life Technologies, Carlsbad, CA, USA). The amplification products were checked by nondenaturing 6% polyacrylamide gel electrophoresis (PAGE), performed in a Sequi-Gen sequencing apparatus (Bio-Rad, Hercules, CA, USA) at constant 55 W, and silver staining. The 50 bp DNA Ladder (Invitrogen) was run in parallel for reference and the evaluation of band size performed with SigmaGel software (SPSS, Blairgowrie, UK). The DD-bands of interest were scratched from the gel and used as template for repeated cycles of amplification and electrophoresis until a single pure band was visualized. Then the PCR products were first purified using the Montage PCR Centrifugal Filter Devices (Millipore, Billerica, MA, USA) followed by treatment with ExoSAP-IT (USB, Cleveland, OH, USA) to remove any unconsumed dNTPs and primers remaining in the PCR product mixture, which could interfere with the sequencing reaction. The purified PCR products were submitted for sequencing by BMR Genomics (Padova, Italy) and DNA sequence similarity was searched with the Nucleotide BLAST algorithm available online.
Messenger RNA expression levels were evaluated by quantitative real-time PCR using Power SYBR Green PCR Master Mix (Applied Biosystems, Philadelphia, PA, USA) as previously described (21) in a 7300 Real Time PCR system (Applied Biosystems) in the presence of 2.5 μM of the primers listed in Table 1 and designed using the Primer3 software available at http://biotools.umassmed.edu/bioapps/primer3_www.cgi. Either GAPDH or β-actin was used as internal control. The PCR data obtained were automatically analyzed by the Relative Quantification Study Software (Applied Biosystem) and expressed as target/reference ratio. Thermocycler conditions were 95 °C for 10 min, followed by 40 cycles of 95 °C for 1 min, and 60 °C for 1 min.
Table 1. Sequence of Primers Used for PCR Amplification
transcript detectedproduct size (bp)oligonucleotides
PKCε2495′-GATCAGAAGGTCACTGCAA-3′
5′-GTCGTCATGGAGGATGGACT-3′
PKCι1695′-TACGGCCAGGAGATACAACC-3′
5′-TCGGAGCTCCCAACAATATC-3
ERGIC-21965′-GCCATGGAGTCTCTGGGATA-3′
5′-CCAAGTCTGAAACGACAGCA-3′
RAD502155′-CTTGGATATGCGAGGACGAT-3′
5′-CCAGAAGCTGGAAGTTACGC-3′
NTRK-21815′-AGCATGAGCACATCGTCAAG-3′
5′-ATATGCAGCATCTGCGACTG-3′
BIG-32315′-CGCCCTGTCTCTAAAACTGC-3′
5′-CTGTCTGCGTTCATCAGCAT-3′
VDUP12235′-TTGTTCTCCCCTTCTGCCAT-3′
5′-AGGGTTGGGCATCTTGATCA-3′
IDI12065′-TTGGGCTGGATAAAACCCCT-3′
5′-ACACAGGCCTTTGTTGTTGT-3′
gelsolin2705′-TGTGATCGAAGAGGTTCCTG-3′
5′-GACCAGTAATCATCATCCCA-3′
β-actin515′-AGGCACCAGGGCGTGAT-3′
5′-GCCCACATAGGAATCCTTCTGAC-3′
GAPDH4145′-CATGGAGGAGGCTGGGGCTC-3′
5′-CACTGACACGTTGGCAGTGG-3′

Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS)

Trypsinized control and HDACi-treated cells were dissolved in a solubilization buffer (0.1 M Tris-HCl, pH 8, 25 mM EGTA, 4% SDS, 1X protease inhibitors cocktail, all purchased from Sigma). Then the samples were sonicated, boiled for 3–5 min, and clarified by centrifugation for 15 min at maximum speed after which the supernatant was collected. The proteins were precipitated using 5 volumes of cold acetone (−20 °C), centrifuged at 13 000 rpm for 10 min at 4 °C, and resuspended in 0.1% SDS before sonication. The protein samples were quantified using the BCA assay kit (Thermo Scientific), and 5 μg was used for tryptic digestion and protein identification for quantitative analysis, whereas 24 μg was used for qualitative analysis. Mass spectrometry was performed as reported by Rozek et al. (22) Briefly, the digested peptides were first applied to a RP-18 trapping column (nanoACQUITY UPLC Symmetry C18 Trap, Waters, Milford, MA, USA) using 0.1% trifluoroacetic acid mobile phase and then to a HPLC RP-18 column (nanoACQUITY UPLC BEH C18 Column, Waters) using an acetonitrile gradient (0–30% in 0.1% formic acid), and the column outlet was directly coupled to the ion source of the Ion Cyclotron Resonance spectrometer (LTQ61 FTICR, Thermo Electron). Each sample was submitted to triplicate LC/MS runs followed by analysis on LTQ OrbitrapVelos (Thermo Scientific, San Jose, CA, USA). The following parameters for dynamic exclusion were applied: 1 repeat count, 30 ms repeat duration, 500 exclusion list size, 120 s exclusion duration, exclusion width low energy 0.51; exclusion width high energy 1.51. The peptides identified in all LC–MS/MS analyses were merged into a common list, which was next overlaid onto 2-D maps generated from the LC/MS profile data of individual samples, as previously reported. (23)

Bioinformatic Analysis

The acquired raw data were processed to produce peak lists by Mascot Distiller software (version 2.2.1, Matrix Science, London, UK). The resulting ion lists were searched using the Mascot search engine (version 2.2.03, Matrix Science) against a database comprising all human protein entries from the Sprot and their reversed versions. The search parameters were as follows: enzyme specificity, trypsin; variable modifications, oxidation (M); and protein mass, unrestricted. The peptide and fragment ion mass tolerances used were 20 ppm and 0.6 Da, respectively. Peptides with Mascot score exceeding the threshold value corresponding to <5% false positive rate calculated by Mascot procedure were considered to be positively identified. At least two peptides for each protein with a score above the threshold were required for the identification. The qualitative analysis of protein/peptide lists generated by the Mascot search engine was performed using MScan, whereas for quantitative estimation the MSparky software tool was used. The statistical analysis was performed using the DiffProt software, thereby obtaining a list of differentially expressed proteins. For each of them the R (ratio) and F (fold change) values were estimated to identify up-/down-regulation and fold changing, respectively. Data are shown as mean ± s.e.m. of independent triplicate experiments. The p values obtained were corrected for multiple-hypothesis testing using a two-step Benjamini–Hochberg procedure that controlled for the false discovery rate. (23) The relative protein abundances with adjusted p values  ≤  0.05 and fold-change (FC) values  ≥ 1.5 were considered as significant in at least one of the studied groups. For graphical summaries and to evaluate the relationships among the studied samples, we used principal component analysis and Ward’s linkage hierarchical clustering. All statistical analyses were performed with MStat software. The software used for bioinformatics analyses were available at http://proteom.ibb.waw.pl/index.en.html.

Comet Assay

The extent of DNA damage in individual cells was established by single cell gel electrophoresis using the OxiSelect Comet assay kit (Cell Biolabs, San Diego, CA, USA) according to the manufacturer’s instructions. Briefly, 1 × 105 MDA-MB231 cells were seeded in 75 cm2 flasks in control conditions or treated with either 8.45 μM JAHA, 2.5 μM etoposide (VP16), or a mixture of the two compounds, for 48 h. At the end of incubation, mechanically detached cells were centrifuged, washed, and resuspended at 1 × 105/mL concentration in Ca++/Mg++-free PBS at 4 °C. The samples were mixed with Comet agarose (1:10 ratio, v/v) and the mixture spread onto the OxiSelect Comet slides and allowed to gel. The slides were then incubated with lysis buffer (4 °C, 45 min in the dark) followed by treatment with an alkaline solution (4 °C, 30 min in the dark) to allow DNA relaxation and denaturation. The damaged DNA was separated by the intact fraction by alkaline gel electrophoresis in an horizontal chamber (15 V, 30 min) in TBE running buffer to detect both single-stranded and double-stranded DNA breaks. At the end of the run, the slides were immersed in cold 70% ethanol for 5 min, air-dried, stained with Vista Green DNA Dye, observed with a Nikon Microphot SA fluorescence microscope, and image analysis performed with CASP Version 1.2.3b1 software (Sourceforge, Diceholdings Inc., New York, NY, USA). Samples were run in triplicate and cells were selected randomly for the analysis per slide. DNA damage was estimated on the basis of tail length (TL), tail moment (TM), olive tail moment (OTM), and % tail DNA (% DNA). Statistical analysis of the data was performed using Excel software.

Results

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To search for differentially expressed genes in MDA-MB231 cells exposed to 8.45 μM HDACis for 18, 24, and 48 h, DD-PCR was performed on enriched mRNA samples isolated from control and treated cell preparations, in the presence of combinations of the arbitrary primers, as listed previously. After PAGE and silver stain, a number of bands appeared differently displayed in parallel control and treated samples, and they were cut from the gel and submitted to further analysis. To this purpose, the cDNA contained in the bands was purified, reamplified until purity and adequate yield, and then the material was submitted to sequencing. Following BLAST analysis, homology was found between six DD-bands and portions of cDNAs of the following genes: (i) Neurotrophic tyrosine kinase, receptor, type 2 (NTRK-2 a.k.a. TRKB, NM_001018064.1), and (ii) RAD50 DNA repair protein (NM_005732.3) both in 24 h-exposure preparations; (iii) Brefeldine A-inhibited guanine nucleotide-exchange protein 3 (BIG-3, NM_020340.3), (iv) Protein kinase C epsilon (PKCε, NM_005400.2), (v) Protein kinase C iota (PKCι; NM_002740.5), (vi) Endoplasmic reticulum–Golgi intermediate compartment 2KDa protein (ERGIC-2, NM_016570.2), all in 48 h exposure preparations.
Real time PCR assays were carried out to validate the DD-PCR data since it is known that the technique may give false positive results; in addition, to confirm the specificity of the HDACi-linked gene signatures, the expression of the genes differentially displayed in case of either conditions of exposure was cross-checked also in parallel control- and treated cell preparations obtained after exposure to the other inhibitor. As shown in Figure 1, JAHA at 8.45 μM concentration prominently induced the expression of RAD50 and NTRK-2 genes after 24 h of treatment, while it reduced the expression of PKCε after 48 h of treatment; on the other hand, the data obtained with SAHA at the same concentration show a clear reduction in the expression levels of BIG-3, PKCι, and ERGIC-2 genes after 48 h of treatment. Noteworthy, the cross-check test demonstrated a drastic down-regulation of PKCε also in MDA-MB231 cells treated for 48 h with SAHA. No significant change was found in the expression levels of RAD50 and NTRK2 in SAHA-exposed cells and of BIG-3, PKCι, and ERGIC-2 in JAHA-exposed cells.

Figure 1

Figure 1. Quantitative real-time PCR analysis of the transcript levels of RAD-50, NTRK2, BIG-3, PKCε, PKCι, and ERGIC-2 in MDA-MB231 cells exposed to either 8.45 μM (A) JAHA or (B) SAHA for 24 h (RAD-50 and NTRK2) or 48 h (BIG-3, PKCε, PKCι, and ERGIC-2). Beta-actin was used as an internal control. Values are the mean ± s.e.m. of two quadruplicate experiments. ∗ indicates p < 0.01 (student’s t test).

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Previous literature data (4) reported that SAHA-exposed MDA-MB231 cells developed up-regulation of some genes associated with differentiation and/or growth inhibition, that is, those encoding for gelsolin, isopentenyl-diphosphate delta isomerase-1 (IDI1), and 1,25-dihydroxyvitamin D-3 up-regulated protein-1 (VDUP1). To extend the comparative evaluation of the molecular effects of SAHA and JAHA inhibitors on MDA-MB231 cells, we checked by real time PCR the effects of MDA-MB231 cell treatment with 8.45 μM JAHA for 48 h on the expression levels of the same genes identified as up-regulated in SAHA-treated cells. The results obtained show a similarity of action of SAHA and JAHA on the expression levels of the genes examined (Figure 2).

Figure 2

Figure 2. Quantitative real-time PCR analysis of the transcript levels of gelsolin, IDI1, and VDPU1 in MDA-MB231 cells exposed to 8.45 μM JAHA for 48 h. Beta-actin was used as an internal control. Values are the mean ± s.e.m. of two quadruplicate experiments. ∗ indicates p < 0.01 (student’s t test).

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To expand the search of JAHA-associated signatures at the protein level, proteomic analyses were performed and showed a differential expression of 11 proteins (six, one, and four associated to 18, 24, and 48 h of treatment with JAHA at 8.45 μM, respectively). As shown in Table 2, of the six proteins associated to 18 h-treatment, four were down-regulated (i.e., Neuroblast differentiation-associated protein AHNAK protein, High mobility group protein B2, Cystatin-B, High mobility group protein B1) and two were up-regulated (i.e., Ribosome-binding protein 1, Glutaredoxin-1) in treated samples. A single up-regulated protein (i.e., Hematological and neurological expressed 1 protein a.k.a. HN1) was found in cells treated with JAHA for 24 h, and four up-regulated proteins in cells treated with JAHA for 48 h (i.e., Prelamin-A/C, Ribosome-binding protein 1, Sulfiredoxin-1, Histone H1.0).
Table 2. Differentially-Expressed Proteins Identified in MDA-MB231 Cells Cultured in Control Conditions and Exposed to 8.45 μM JAHA for 18, 24, and 48 h
accession no.proteinQ valueratio (control/treated)fold changepeptides
18 h
Q09666Neuroblast differentiation-associated protein AHNAK0.000791.351.35276
P26583High mobility group protein B20.001582.442.4412
P04080Cystatin-B (a.k.a Stefin-B)0.024222.942.947
Q9P2E9Ribosome-binding protein 1 (RRBP1)0.025870.611.6422
P09429High mobility group protein B10.081122.702.7011
P35754Glutaredoxin-10.089780.482.095
24 h
Q9UK76Hematological and neurological expressed 1 protein (HN1)0.022260.442.2610
48 h
P02545Prelamin-A/C0.000750.52.0036
Q9P2E9Ribosome-binding protein 1 (RRBP1)0.010570.422.3624
Q9BYN0Sulfiredoxin-10.041550.128.553
P07305Histone H1.00.045780.205.056
Twenty-two proteins appeared to be differentially expressed in cells treated with SAHA at the same concentration (16, 5, and 1, respectively, associated to 18, 24, and 48 h-treatment). Of the 16 proteins identified at 18 h-treatment, six were down-regulated (i.e., Reticulocalbin-1, Microtubule-associated protein 1B, Caprin-1, Spectrin α chain nonerythrocytic 1, Integrin β1, Myristoylated alanine-rich C-kinase substrate), whereas the other ones were up-regulated in the treated samples (i.e., Histone H1.0, Neuroblast differentiation-associated protein AHNAK, Hematological and neurological expressed protein 1 a.k.a. HN1, Nucleolar and coiled-body phosphoprotein 1, Nucleolin, Eukaryotic translation initiation factor 4H, 78 kDa Glucose-regulated protein, Histidine triad nucleotide-binding protein 2 mitochondrial, Na+/H+ exchange regulatory cofactor NHE-RF1, Nonerythrocytic spectrin alpha chain 1, Integrin β1, Heterogeneous nuclear ribonucleoproteins A2/B1). Of the five proteins associated to 24 h-treatment, two were down-regulated (i.e., Neuroblast differentiation-associated protein AHNAK, Nicotinamide phosphoribosyltransferase) and three were up-regulated (i.e., Na+/H+ exchange regulatory cofactor NHE-RF1, Histone H1, 78 kDa Glucose-regulated protein). Finally, a single protein was identified as down-regulated (Neuroblast differentiation-associated protein AHNAK) in the samples treated with the inhibitor for 48 h (Table 3).
Table 3. Differentially-Expressed Proteins Identified in MDA-MB231 Cells Cultured in Control Conditions and Exposed to 8.45 μM SAHA for 18, 24, and 48 h
accession no.proteinQ valueratio (control/treated)fold changepeptides
18h
P07305Histone H1.00.000350.119.036
Q09666Neuroblast differentiation-associated protein AHNAK0.000351.411.41257
Q9UK76Hematological and neurological expressed 1 protein (HN1)0.002800.472.1310
Q15293Reticulocalbin-10.004692.602.6013
Q14978Nucleolar and coiled-body phosphoprotein 10.004890.541.8517
P19338Nucleolin0.005450.511.9628
Q15056Eukaryotic translation initiation factor 4H0.005590.492.047
P46821Microtubule-associated protein 1B0.013892.032.0314
Q14444Caprin-10.015651.751.7511
P1102178 kDa glucose-regulated protein0.016230.641.5635
Q9BX68Histidine triad nucleotide-binding protein 2, mitochondrial0.016790.204.973
O14745Na(+)/H(+) exchange regulatory cofactor NHE-RF10.017760.372.714
Q13813Spectrin alpha chain, nonerythrocytic 10.018491.511.5136
P05556Integrin β10.018771.671.6710
P22626Heterogeneous nuclear ribonucleoproteins A2/B10.020380.551.8114
P29966Myristoylated alanine-rich C-kinase substrate0.053481.981.9810
24 h
Q09666Neuroblast differentiation-associated protein AHNAK0.000721.531.53267
O14745Na+/H+ exchange regulatory cofactor NHE-RF10.005020.263.794
P07305Histone H1.00.018150.541.856
P1102178 kDa glucose-regulated protein0.035860.551.8335
P43490Nicotinamide phosphoribosyltransferase0.059413.043.049
48 h
Q09666Neuroblast differentiation-associated protein AHNAK0.085762.262.26254
The finding that exposure to JAHA induced the selective up-regulation of molecular signatures linked to the processes of DNA repair and response to oxidative stress, such as NTRK-2, RAD50, sulfiredoxin-1, and glutaredoxin-1, prompted to check the related “in cellulo” effect by examining whether the presence of this HDACi could reverse the production of DNA lesions induced by the topoisomerase IIα inhibitor VP16. The genotoxic effect of JAHA was assessed in MDA-MB231 breast cancer cells using Comet assay. The panel in Figure 3 show the very low level of DNA damage in control and 8.45 μM JAHA-treated cells in contrast to 2.5 μM VP16-treated cells, as shown by the mean DNA tail moment indicative of persistent double- and single-strand breaks. Interestingly, DNA damage induced by the latter was reduced by 50% when cells were coexposed to 8.45 μM JAHA and 2.5 μM VP16, as displayed by the decrease of the DNA tail moment. Although, as compared to the basal level of control cells, the total DNA damage appeared not to be entirely reversible by VP16/JAHA cotreatment, nevertheless this result confirms that the DNA repair system was efficiently switched-on in the presence of the HDACi, as suggested by some of the revealed molecular signatures associated with exposure of MDA-MB231 breast cancer cells to JAHA.

Figure 3

Figure 3. (A) Representative micrographs of cell comets obtained from MDA-MB231 TNBC cells stained with Vista Green DNA Dye, observed with a Nikon Microphot SA fluorescence microscope: (a) control cells, (b) cells treated with 2.5 μM VP16 for 48 h, (c) cells treated with 8.45 μM JAHA for 48 h, and (d) cells cotreated with 8.45 μM JAHA and 2.5 μM VP16 for 48 h. Microscopic magnification = 400×. (B) Histograms showing the olive tail moment of the scored cells exposed to VP16, JAHA, and VP16/JAHA, as compared to control (n = 60 for each experimental condition). Values are the mean ± s.e.m. of the results obtained. ∗ indicates p < 0.05 (student’s t test).

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Discussion

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Breast tumor is a widely spread neoplastic histotype accounting for about 20% of all cancers in women; about 15% of breast cancers are TNBC and the lack of receptors for estrogens, progesterone, and epidermal growth factor renders neoplastic cells highly aggressive and endowed with a higher malignant potential than other breast tumor subtypes (e.g., ref 24). Since the pharmacological options for treating TNBC are limited, there has been great interest in testing novel drugs or analogues of pre-existing drugs counteracting TNBC cell growth, which, on the other hand, necessitates a comprehensive biological characterization. The effects of the HDACi JAHA on aspects of the biology of TNBC MDA-MB231 cells, such as survival, cell cycle, mitochondrial activity, autophagy, apoptosis, and signal transduction, have been the object of previous publications. (16, 25) Since it is widely acknowledged that multiplatform classification of breast cancers is based on genomic sequencing, gene expression profiling, and proteomics, the present study was focused on the evaluation of some molecular aspects of the effects exerted by JAHA on this cell line, also comparing with those related to exposure to the parental HDACi SAHA.
For this reason, to supplement the catalogue of JAHA- (and in parallel SAHA-) dependent genes and search for putative molecular markers linked to the lethal action of JAHA, cDNA samples obtained from enriched mRNA preparations of MDA-MB231 cells, both control and treated with the HDACis, were submitted to DD-PCR assay and the results obtained were confirmed by real time-PCR assay. In parallel, protein extracts from control and exposed cells were comparatively studied via mass spectrometry and bioinformatics. The results obtained indicate that under the same experimental conditions JAHA and SAHA, although sharing some common aspects, induce a diversified molecular reprogramming and allow one to draw the following conclusions.
Exposure of cells to JAHA appeared to selectively trigger an early and approximately four-fold overexpression of two oxidative-stress related genes, that is, NTRK-2 and RAD-50. The former encodes for a member of the tropomyosin-related kinase family of neurotrophin receptors, which is up-regulated in several human cancers, including TNBC, where it was found to be involved in epithelial-mesenchymal transition, anoikis resistance, and metastatic spread. (26, 27) In addition, a number of studies performed on nerve and choriocarcinoma cell models have demonstrated its powerful role in repair of oxidative DNA damage and related inhibition of apoptosis. In particular, in rat cortical neurons the NTRK-2 protective activity was found to be accomplished via PI3K, pAKT, pCREB, and the expression of APE1 (apurinic/apyrimidinic endonuclease-1), a key component of the base excision DNA repair pathway. (28, 29) RAD-50 is known to participate with MRE11 and NBS1 to the formation of the MRN complex, which coordinates the repair of DNA double strand breaks in the nucleus. (30) The inability of SAHA to trigger RAD50 up-regulation was demonstrated also in prostate cancer cells by Lee et al., (31) thereby further confirming that this is a JAHA-selective gene signature. Evidence of JAHA’s role as antioxidative stress compound emerged also from proteomic analyses demonstrating the specific accumulation of glutaredoxin-1, cystatin-B, and, more prominently and at a later time, sulfiredoxin-1. The latter one is an ATP-dependent cytoprotective antioxidant enzyme known to catalyze peroxiredoxin reactivation and deglutathionylation of glutathionylated proteins in several cytotypes exposed to diversified chemical and biological stimuli that elicit the production of reactive oxygen species. (32) Glutaredoxin-1 catalyzes the reversible reduction of glutathione-protein mixed disulfides and is implicated in DNA repair and mitochondrial DNA synthesis, thereby highly contributing to the antioxidant cellular defense system. (33) Cystatin-B is an inhibitor of lysosomal cysteine cathepsin that has been proven to protect mouse mammary tumor cells from oxidative stress and consequent death. (34) The ability of JAHA to reverse DNA damage in cultured cells, at least in part, was demonstrated by a Comet assay in JAHA/VP16 cotreatment experiments thereby further substantiating that there is a correlation between the increase of the molecular signatures involved in DNA repair mechanisms and the peculiar ability of JAHA to reduce DNA damage, through a molecular mechanism, which is still to be determined. Noteworthy, this finding is contrary to what has been described as a general aspect of HDACis, (35) that is, the inhibition of different aspects of DNA repair including the interference with coordination of ataxia-telangiectasia and Rad3-related (ATR) activation and signaling, which is downstream Rad50 phosphorylation; (36) this peculiar property of JAHA seems truly interesting since it is uncommon but beneficial to find a HDACi that simultaneously increases DNA repair. Other specific JAHA signatures are represented by the early down-regulation of the high mobility group proteins and the up-regulation of RRBP1 that continues also in later time coupled with the late up-regulation of prelamin A/C. The first ones are architectural transcription factors, and a miRNA-triggered decrease of the amount of high mobility group protein-B1 has been proven to impair MDA-MB231 cell cycle progression and render these and other mammalian cytotypes sensitive to a number of diversified death stimuli. (37, 38) Noteworthy, high mobility group proteins-B1 and -B2 are known to play a DNA damage-sensing role and induce phosphorylation of p53 as a response; (39) therefore, the decrease of the intracellular amount of these chromatin-associated factors may be responsible, at least in part, of the previously observed lack of apoptosis induction after cell exposure to JAHA. (25) On the other hand, apoptosis restraining could also result from constant RRBP1 accumulation; this ribosome-binding factor is associated with unfolded protein response in the endoplasmic reticulum and its up-regulation has been found to render lung cancer cells more resistant to the stress and to alleviate apoptosis. (40) Accumulation of prelamin A-C is indicative of impairment of protein farnesylation which is a prerequisite for its processing. (41) It is known that farnesylated species are cytotoxic, and in particular the accumulation of prelamin A in fibroblasts by siRNA transfection has been shown to increase the levels of reactive oxygen species, affect mitochondrial respiration, and alter the expression of the genes encoding detoxifying enzymes. (42) In addition, it is worth mentioning that farnesylation represents a maturation step for Ras GTPase, (43) and therefore, if JAHA determines in some way the inhibition of farnesyltransferase activity as suggested by accumulation of prelamin, it may exert its lethal effect by also targeting other substrates that play pivotal roles in the control of cell survival and growth.
A number of molecular signatures were shared between JAHA and SAHA. DD-PCR experiments demonstrated that the two HDACis were able to induce a late PKCε down-regulation. It is known that the down-regulation of this protein in MDA-MB231 cells accounts for a reduced transcriptional activity of NF-κB due to a significant inhibition of nuclear translocation of p65. This may lead to the alteration of the expression of genes involved in cell survival and proliferation, (44) which may be one of the aspects involved in the already-observed perturbation of MDA-MB231 cell cycle by JAHA, (25) and expands the list of shared gene signatures associated with differentiation or growth inhibition, such as gelsolin, IDI1, and VDUP1. From proteomic analyses, it appeared that JAHA and SAHA shared also a decrease of the amount of the neuroblast differentiation-associated protein AHNAK, more prolonged in the presence of SAHA, and the increase of the amount of histone H1.0, earlier in the presence of SAHA, and of HN1. Also histone H1.0 and HN1 represent growth-associated factors. It is already known that histone H1.0 gene expression is sensitive to the state of chromatin acetylation, and in particular to the inhibition of HDAc, as found for trichostatin A-treated mouse mammary tumor cells. (45) An immunohistochemical study on breast cancer specimens of different histological grading has strongly suggested that histone H1.0 expression is linked to a prolongation of cell intermitotic period irrespective of cell malignant potential, thereby representing a marker of a low proliferative activity. (46) On the other hand, HN1, which is an interaction partner of the inactive GSK3β/β-catenin/APC complex contributing to ubiquitin-dependent proteasomal degradation of β-catenin, when overexpressed in prostate cancer cells have been shown to trigger their accumulation at G2/M checkpoint, and to reduce the proliferation rate. (47) These literature data are consistent with our previous results (25) demonstrating cell cycle perturbation and a delay in G2/M transition in MDA-MB231 cells exposed to JAHA. Various are the intracellular roles played by the giant AHNAK protein in very diverse biological processes. (48) In breast cancer, this protein was found to be localized in lipid rafts thus suggesting its involvement in signaling pathways also linked with the reorganization of actin submembraneous network. (49) In particular, when AHNAK was overexpressed in TNBC cell lines, such as MDA-MB231, a marked inhibition of ERK phosphorylation was observed; therefore, it is conceivable that JAHA-mediated AHNAK down-regulation in this cell line may be at least in part responsible of the observed early reduction of the amount of pERK in MDA-MB231 wells exposed to JAHA, as reported by Librizzi et al. (16)
A number of genes and, more prominently, protein signatures, involved in different biological events have been found associated only to SAHA-, and not JAHA-, treatment under the same experimental conditions. Thus, as opposed to SAHA, JAHA did not appear to be active on the control of specific enzyme activities via (i) the down-regulation of the expression of BIG-3 encoding for an A-kinase anchoring protein, (50) and of PKCι whose depletion have been proven to restrain TNBC growth and address cells to senescence, (51, 52) (ii) the increase of accumulation of eukaryotic translation initiation factor 4H, an activator of the RNA helicase eIF4A, (53) and (iii) the decrease of the amount of nicotinamide phosphoribosyltransferase, whose inhibition was found to suppress breast tumor growth in vivo in a xenograft model. (54) Other biological mediators whose expression/accumulation was affected by SAHA, but not JAHA, are (i) the proliferation- and cell cycle-affecting factors ERGIC-2, (55) myristoylated alanine-rich C-kinase substrate, (56) nucleolin, (57) nucleolar and coiled-body phosphoprotein 1, (58) reticulocalbin-1, (59) spectrin alpha chain, nonerythrocytic 1, (60) and caprin-1, (61) (ii) the autophagy marker microtubule-associated protein 1B, (62) (iii) the endoplasmic reticulum chaperone 78 kDa glucose-regulated protein, (63) and (iv) signaling molecules such as the extracellular matrix receptor subunit integrin β1, (64) the ERK-activating factor heterogeneous nuclear ribonucleoproteins A2/B1, (65) the EGFR regulator Na(+)/H(+) exchange regulatory cofactor NHE-RF1, (66) and the inhibitor of Wnt/β-catenin pathway histidine triad nucleotide-binding protein 2. (67)
In summary, in this study we have established a number of molecular signatures in response to the HDACi JAHA in a TNBC cell model, and although this compound is closely related to the parental molecule SAHA, we have revealed some substantial differences in the biomarkers of drug responses. In contrast to the more numerous and diversified changes induced by SAHA, JAHA displays a more selective impact on the expression of molecular signatures by increasing the expression of some molecular signatures involved in antioxidant activity and DNA repair. This specific property will represent a challenge, which must be taken into account in a future consideration of this molecule as an anticancer drug. Literature data have already reported the effect of SAHA or other HDACis on only five among the molecular signatures identified in this study, that is, 78 kDa glucose-regulated protein, integrin β1, NHE-RF1, reticulocalbin-1, and histone H1.0. (68-72) Therefore, our work also contributes to expand the list of molecular signature responsive to cell exposure to these enzyme inhibitors. On the basis of the present exploratory study, further work using global gene expression and proteomic profiling protocols will allow a further understanding of the selective molecular response associated with their mechanisms of action, and to define key client transcripts and proteins for either specific compound with potential clinical significance minimizing the problematic effects and emphasizing the therapeutic ones.

Author Information

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  • Corresponding Authors
    • Fabio Caradonna - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy;  Orcidhttp://orcid.org/0000-0002-7659-7312;  Email: [email protected]
    • Janusz Dębski - Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
    • Michał Dadlez - Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland;  Orcidhttp://orcid.org/0000-0002-8749-9224
  • Authors
    • Mariangela Librizzi - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy
    • Ilenia Cruciata - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy
    • Supojjanee Sansook - Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, United Kingdom
    • John Spencer - Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, United Kingdom;  Orcidhttp://orcid.org/0000-0001-5231-8836
    • Claudio Luparello - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy;  Orcidhttp://orcid.org/0000-0001-9821-5891
  • Author Contributions

    The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

  • Funding

    Work was partly funded by University of Palermo/Italy (FFR 2013), the Italian Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (PON 01_01059.) to C.L. and M.L., and the Royal Thai Government to S.S.

  • Notes
    The authors declare no competing financial interest.

Abbreviations

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HDACi

histone deacetylase inhibitor

SAHA

suberoylanilide hydroxamic acid

TNBC

triple-negative breast cancer

JAHA

Jay Amin hydroxamic acid

IC50

half maximal inhibitory concentration

pERK

phosphorylated extracellular signal-related kinase

DNMT

DNA methyltransferase

PCR

polymerase chain reaction

EDTA

ethylenediaminetetraacetic acid

DD

differential display

PAGE

polyacrylamide gel electrophoresis

dNTP

deoxynucleotide triphosphate

GAPDH

glyceraldehyde 3-phosphate dehydrogenase

EGTA

ethylene-bis (oxyethylenenitrilo) tetraacetic acid

SDS

sodium dodecyl sulfate

BCA

bicinchoninic acid

HPLC

high performance liquid chromatography

LC–MS/MS

liquid chromatography–tandem mass spectrometry

s.e.m.

standard error of the mean

NTRK-2

neurotrophic tyrosine kinase, receptor, type 2

BIG-3

brefeldine A-inhibited guanine nucleotide-exchange protein 3

PKCε

protein kinase C epsilon

PKCι

protein kinase C iota

ERGIC-2

endoplasmic reticulum-Golgi intermediate compartment 2KDa protein

IDI1

isopentenyl-diphosphate delta isomerase-1

VDUP1

1,25-dihydroxyvitamin d-3 up-regulated protein-1

RRBP1

ribosome-binding protein 1

HN1

hematological and neurological expressed 1 protein

NHE-RF1

Na(+)/H(+) exchange regulatory cofactor

PI3K

phosphatidylinositol-4,5-bisphosphate 3-kinase

pCREB

phosphorylated cyclic AMP response element binding

APE1

apurinic/apyrimidinic endonuclease-1

MRN

Mre11-Rad50-Nbs1

siRNA

short interfering RNA

GSK3β

glycogen synthase kinase 3 beta

APC

adenomatous polyposis coli

EGFR

epidermal growth factor receptor

ATR

ataxia-telangiectasia and Rad3-related

References

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  10. 10
    Marzenell, P., Hagen, H., Sellner, L., Zenz, T., Grinyte, R., Pavlov, V., Daum, S., and Mokhir, A. (2013) Aminoferrocene-based prodrugs and their effects on human normal and cancer cells as well as bacterial cells J. Med. Chem. 56, 6935– 6944 DOI: 10.1021/jm400754c
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    10
    Aminoferrocene-Based Prodrugs and Their Effects on Human Normal and Cancer Cells as Well as Bacterial Cells
    Marzenell, Paul; Hagen, Helen; Sellner, Leopold; Zenz, Thorsten; Grinyte, Ruta; Pavlov, Valeri; Daum, Steffen; Mokhir, Andriy
    Journal of Medicinal Chemistry (2013), 56 (17), 6935-6944CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Aminoferrocene-based prodrugs are activated under cancer-specific conditions (high concn. of reactive oxygen species, ROS) with the formation of glutathione scavengers (p-quinone methide) and ROS-generating iron complexes. Herein, the authors explored three structural modifications of these prodrugs to improve their properties: (a) the attachment of a -COOH function to the ferrocene fragment leads to the improvement of water soly. and reactivity in vitro but also decreases cell-membrane permeability and biol. activity, (b) the alkylation of the N-benzyl residue does not show any significant affect, and (c) the attachment of the second arylboronic acid fragment improves the toxicity (IC50) of the prodrugs toward human promyelocytic leukemia cells (HL-60) from 52 to 12 μM. Finally, the authors demonstrated that the prodrugs are active against primary chronic lymphocytic leukemia (CLL) cells, with the best compds. exhibiting an IC50 value of 1.5 μM. The most active compds. were found to not affect mononuclear cells and representative bacterial cells.
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  11. 11
    Jaouen, G., Vessières, A., and Top, S. (2015) Ferrocifen type anti cancer drugs Chem. Soc. Rev. 44, 8802– 8817 DOI: 10.1039/C5CS00486A
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    11
    Ferrocifen type anti cancer drugs
    Jaouen, Gerard; Vessieres, Anne; Top, Siden
    Chemical Society Reviews (2015), 44 (24), 8802-8817CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    Despite current developments in therapeutics focusing on biotechnol.-oriented species, the unflagging utility of small mols. or peptides in medicine is still producing strong results. In 2014 for example, of the 41 new medicines authorized for sale, 33 belonged to the category of small mols., while in 2013 they represented 24 of 27, according to the FDA. This can be explained as the result of recent forays into new or long-neglected areas of chem. Medicinal organometallic chem. can provide us with an antimalarial against resistant parasitic strains, as attested by the phase II clin. development of ferroquine, with a new framework for conceptual advances based on three-dimensional space-filling, and with redox or indeed catalytic intracellular properties. In this context, bioferrocene species with antiproliferative potential have for several years been the subject of sustained effort, based on some initial successes and on the nature of ferrocene as a stable arom., with low toxicity, low cost, and possessing reversible redox properties. We show here the different antitumoral approaches offered by ferrocifen derivs., originally simple derivs. of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity. These entities act via various targets, some of which have been identified, that are triggered according to the concn. of the products. They also act according to the nature of the cancer cells and their functionality, by mechanistic pathways that can operate either synergistically or not, in successive, concomitant or sequential ways, depending for example on newly identified signaling pathways inducing senescence or apoptosis. Here we present a first attempt to rationalize the behavior of these entities with various anticancer targets.
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  12. 12
    Leonidova, A., Anstaett, P., Pierroz, V., Mari, C., Spingler, B., Ferrari, S., and Gasser, G. (2015) Induction of cytotoxicity through photorelease of aminoferrocene Inorg. Chem. 54, 9740– 9748 DOI: 10.1021/acs.inorgchem.5b01332
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    12
    Induction of Cytotoxicity through Photorelease of Aminoferrocene
    Leonidova, Anna; Anstaett, Philipp; Pierroz, Vanessa; Mari, Cristina; Spingler, Bernhard; Ferrari, Stefano; Gasser, Gilles
    Inorganic Chemistry (2015), 54 (20), 9740-9748CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    Reactive oxygen species (ROS)-activated aminoferrocene-based anticancer prodrug candidates successfully take advantage of intrinsically high amts. of ROS in tumor tissues. Interestingly, the ROS-initiated activation of these prodrug candidates leads to formation of unstable aminoferrocene (Fc-NH2) derivs., which decay to iron ions. The latter catalytically increases ROS concn. to a lethal level. In this work, we prepd. light-controlled aminoferrocene prodrug candidates by derivatizing Fc-NH2 with an o-nitrophenyl and an o-nitrobiphenyl photolabile protecting group (PLPG), resp., and by further conjugation to a mitochondria localization signal (MLS) peptide (Cys-D-Arg-Phe-Lys-NH2). The resulting bioconjugates were found to be more stable and less cytotoxic, in the dark, toward human promyelocytic leukemia cells (HL-60) compared to Fc-NH2. Upon light irradn. at 355 nm, both conjugates released Fc-NH2, albeit with very different photolysis quantum yields. The o-nitrobiphenyl photocage was in fact several orders of magnitude more efficient than the o-nitrophenyl photocage in releasing Fc-NH2. This difference was reflected by the light irradn. expts. on the HL-60 cell line, in which aminoferrocene conjugated with the o-nitrobiphenyl cage and the MLS displayed the highest phototoxicity index (2.5 ± 0.4) of all the compds. tested. The iron release assays confirmed the rise in iron ion concns. upon light irradn. of both caged aminoferrocene derivs. Together with the absence of phototoxicity on the nonmalignant hTERT-immortalized retinal pigment epithelial (hTERT RPE-1) cell line, these results indicate catalytic generation of ROS as possible mode of action.
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    Patra, M. and Gasser, G. (2017) The medicinal chemistry of ferrocene and its derivatives Nat. Rev. Chem. 1, 0066 DOI: 10.1038/s41570-017-0066
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    13
    The medicinal chemistry of ferrocene and its derivatives
    Patra, Malay; Gasser, Gilles
    Nature Reviews Chemistry (2017), 1 (9), 0066CODEN: NRCAF7; ISSN:2397-3358. (Nature Research)
    A review. Ferrocene derivs. have attracted significant interest as anticancer, antibacterial, antifungal and antiparasitic drug candidates. Discovered in the 1990s, the two most prominent derivs., ferroquine and ferrocifen, have since been studied extensively for the treatment of malaria and cancer, resp. The ferrocenyl moiety in these two compds. participates in important metal-specific modes of action that contribute to the overall therapeutic efficacy of the mols. Although ferroquine is currently in phase II clin. trials and ferrocifen is in preclin. evaluation, no other ferrocene deriv. - in fact, no other non-radioactive organometallic compd. of any kind - has advanced into clin. trials. This Perspective delineates strategies for the systematic incorporation of ferrocenyl groups into known drugs or drug candidates, with a view to finding new drug leads. In addn., we provide a crit. evaluation of the difficulties assocd. with obtaining the clin. approval that would enable ferrocene-contg. mols. to transition from being synthetic curiosities to effective drugs.
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  14. 14
    Ocasio, C. A., Sansook, S., Jones, R., Roberts, J. M., Scott, T. G., Tsoureas, N., Coxhead, P., Guille, M., Tizzard, G. J., Coles, S. J., Hochegger, H., Bradner, J. E., and Spencer, J. (2017) Organometallics 36, 3276– 3283 DOI: 10.1021/acs.organomet.7b00437
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    Li, J., Liu, R., Lei, Y., Wang, K., Lau, Q. C., Xie, N., Zhou, S., Nie, C., Chen, L., Wei, Y., and Huang, C. (2010) Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells Autophagy 6, 711– 724 DOI: 10.4161/auto.6.6.12397
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    Librizzi, M., Chiarelli, R., Bosco, L., Sansook, S., Gascon, J. M., Spencer, J., Caradonna, F., and Luparello, C. (2015) The histone deacetylase inhibitor JAHA down-regulates pERK and global DNA methylation in MDA-MB231 breast cancer cells Materials 8, 7041– 7047 DOI: 10.3390/ma8105358
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    Sirchia, R. and Luparello, C. (2009) Short-term exposure to cadmium affects the expression of stress response and apoptosis-related genes in immortalized epithelial cells from the human breast Toxicol. In Vitro 23, 943– 949 DOI: 10.1016/j.tiv.2009.04.016
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    Luparello, C., Longo, A., and Vetrano, M. (2012) Exposure to cadmium chloride influences astrocyte-elevated gene-1 (AEG-1) expression in MDA-MB231 human breast cancer cells Biochimie 94, 207– 213 DOI: 10.1016/j.biochi.2011.10.009
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    Luparello, C., Sirchia, R., and Longo, A. (2013) Type V collagen and protein kinase C η down-regulation in 8701-BC breast cancer cells Mol. Carcinog. 52, 348– 358 DOI: 10.1002/mc.21856
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    Type V collagen and protein kinase C η down-regulation in 8701-BC breast cancer cells
    Luparello, Claudio; Sirchia, Rosalia; Longo, Alessandra
    Molecular Carcinogenesis (2013), 52 (5), 348-358CODEN: MOCAE8; ISSN:0899-1987. (Wiley-Blackwell)
    We previously reported that ductal infiltrating carcinomas (d.i.c.) of the human breast display profound modifications of the stromal architecture, assocd. with anomalous collagen compn. Among the major alterations obsd. in the interstitial collagen, the relative increase of type V collagen content was detected. When type V collagen was used as an "in vitro" substrate for 8701-BC d.i.c. cells, it appeared able to restrain cell growth, inhibit cell motility and invasion "in vitro", and modify the expression levels of genes coding for apoptosis factors, caspases and stress response proteins. In the present paper we demonstrate that type V collagen induces the down-regulation of protein kinase C η, an event that may be, at least in part, responsible of the previously-reported modifications of cell morphol. and growth rate, and that appears to be involved in the already-obsd. changes of expression levels of genes encoding for anti- (Bcl-2) and pro-apoptotic factors (Bad, Dapk, Bcl-Xs) and enzymes (caspase 5 and 8). © 2011 Wiley Periodicals, Inc.
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  20. 20
    Sokolov, B. P. and Prockop, D. J. (1994) A rapid and simple PCR-based method for isolation of cDNAs from differentially expressed genes Nucleic Acids Res. 22, 4009– 4015 DOI: 10.1093/nar/22.19.4009
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    Naselli, F., Belshaw, N. J., Gentile, C., Tutone, M., Tesoriere, L., Livrea, M. A., and Caradonna, F. (2015) Phytochemical indicaxanthin inhibits colon cancer cell growth and affects the DNA methylation status by influencing epigenetically modifying enzyme expression and activity J. Nutrigenet. Nutrigenomics 8, 114– 127 DOI: 10.1159/000439382
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    21
    Phytochemical Indicaxanthin Inhibits Colon Cancer Cell Growth and Affects the DNA Methylation Status by Influencing Epigenetically Modifying Enzyme Expression and Activity
    Naselli, Flores; Belshaw, Nigel Junior; Gentile, Carla; Tutone, Marco; Tesoriere, Luisa; Livrea, Maria Antonietta; Caradonna, Fabio
    Journal of Nutrigenetics and Nutrigenomics (2015), 8 (3), 114-127CODEN: JNNOBS; ISSN:1661-6499. (S. Karger AG)
    Background: Recently, we have shown anti-proliferative and pro-apoptotic effects of indicaxanthin assocd. with epigenetic modulation of the onco-suppressor p16INK4a in the human colon cancer cell line CACO2. In the present study, the epigenetic activity of indicaxanthin and the mechanisms involved were further investigated in other colorectal cancer cell lines. Methods: LOVO1, CACO2, HT29, HCT116, and DLD1 cells were used to evaluate the potential influence of consistent dietary concns. of indicaxanthin on DNA methylation, and the epigenetic mechanisms involved were researched. Results: Indicaxanthin exhibited anti-proliferative activity in all cell lines but HT29, induced demethylation in the promoters of some methylation-silenced onco-suppressor genes involved in colorectal carcinogenesis (p16INK4a, GATA4, and ESR1), and left unchanged others which were basally hypermethylated (SFRP1 and HPP1). In apparent contrast, cell exposure to indicaxanthin increased DNMT gene expression, although indicaxanthin appeared to be an inhibitor of DNMT activity. Indicaxanthin also increased the expression of genes involved in DNA demethylation. Finally, an in silico mol. modeling approach suggested stable binding of indicaxanthin at the DNMT1 catalytic site. Conclusions: Our findings contribute to new knowledge in the field of phytochems. and specifically suggest dietary indicaxanthin as a potential epigenetic agent to protect colon cells against tumoral alterations.
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  22. 22
    Rozek, W., Kwasnik, M., Debski, J., and Zmudzinski, J. F. (2013) Mass spectrometry identification of granins and other proteins secreted by neuroblastoma cells Tumor Biol. 34, 1773– 1781 DOI: 10.1007/s13277-013-0716-0
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    22
    Mass spectrometry identification of granins and other proteins secreted by neuroblastoma cells
    Rozek, Wojciech; Kwasnik, Malgorzata; Debski, Janusz; Zmudzinski, Jan F.
    Tumor Biology (2013), 34 (3), 1773-1781CODEN: TUMBEA; ISSN:1010-4283. (Springer)
    We used mass spectrometry-based protein identification to det. the presence of granins and other proteins in the mouse neuroblastoma secretome. We detected polypeptides derived from four members of the granin family: chromogranin A, chromogranin B, secretogranin III, and VGF. Many of them are derived from previously described biol. active regions; however, for VGF and CgB, we detected peptides not related to known bioactivities. Along with granins, we identified 115 other proteins secreted by mouse neuroblastoma cells, belonging to different functional categories. Fifty-six out of 119 detected proteins possess the signal fragments required for translocation into endoplasmic reticulum. Sequences of remaining 63 proteins were analyzed using SecretomeP algorithm to det. probability of nonclassical secretion. Identified proteins are involved in the regulation of cell cycle, proliferation, apoptosis, angiogenesis, proteolysis, and cell adhesion.
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    Bakun, M., Senatorski, G., Rubel, T., Lukasik, A., Zielenkiewicz, P., Dadlez, M., and Paczek, L. (2014) Urine proteomes of healthy aging humans reveal extracellular matrix (ECM) alterations and immune system dysfunction Age (Dordr.) 36, 299– 311 DOI: 10.1007/s11357-013-9562-7
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    23
    Urine proteomes of healthy aging humans reveal extracellular matrix (ECM) alterations and immune system dysfunction
    Bakun M; Senatorski G; Rubel T; Lukasik A; Zielenkiewicz P; Dadlez M; Paczek L
    Age (Dordrecht, Netherlands) (2014), 36 (1), 299-311 ISSN:.
    Aging is a complex physiological process that poses considerable conundrums to rapidly aging societies. For example, the risk of dying from cardiovascular diseases and/or cancer steadily declines for people after their 60s, and other causes of death predominate for seniors older than 80 years of age. Thus, physiological aging presents numerous unanswered questions, particularly with regard to changing metabolic patterns. Urine proteomics analysis is becoming a non-invasive and reproducible diagnostic method. We investigated the urine proteomes in healthy elderly people to determine which metabolic processes were weakened or strengthened in aging humans. Urine samples from 37 healthy volunteers aged 19-90 years (19 men, 18 women) were analyzed for protein expression by liquid chromatography-tandem mass spectrometry. This generated a list of 19 proteins that were differentially expressed in different age groups (young, intermediate, and old age). In particular, the oldest group showed protein changes reflective of altered extracellular matrix turnover and declining immune function, in which changes corresponded to reported changes in cardiovascular tissue remodeling and immune disorders in the elderly. Thus, urinary proteome changes in the elderly appear to reflect the physiological processes of aging and are particularly clearly represented in the circulatory and immune systems. Detailed identification of "protein trails" creates a more global picture of metabolic changes that occur in the elderly.
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    Gluz, O., Liedtke, C., Gottschalk, N., Pusztai, L., Nitz, U., and Harbeck, N. (2009) Triple-negative breast cancer - current status and future directions Ann. Oncol. 20, 1913– 1927 DOI: 10.1093/annonc/mdp492
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    24
    Triple-negative breast cancer--current status and future directions
    Gluz O; Liedtke C; Gottschalk N; Pusztai L; Nitz U; Harbeck N
    Annals of oncology : official journal of the European Society for Medical Oncology (2009), 20 (12), 1913-27 ISSN:.
    Triple-negative breast cancer (TNBC) is defined by a lack of expression of both estrogen and progesterone receptor as well as human epidermal growth factor receptor 2. It is characterized by distinct molecular, histological and clinical features including a particularly unfavorable prognosis despite increased sensitivity to standard cytotoxic chemotherapy regimens. TNBC is highly though not completely concordant with various definitions of basal-like breast cancer (BLBC) defined by high-throughput gene expression analyses. The lack in complete concordance may in part be explained by both BLBC and TNBC comprising entities that in themselves are heterogeneous. Numerous efforts are currently being undertaken to improve prognosis for patients with TNBC. They comprise both optimization of choice and scheduling of common cytotoxic agents (i.e. addition of platinum salts or dose intensification strategies) and introduction of novel agents (i.e. poly-ADP-ribose-polymerase-1 inhibitors, agents targeting the epidermal growth factor receptor, multityrosine kinase inhibitors or antiangiogenic agents).
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    Librizzi, M., Longo, A., Chiarelli, R., Amin, J., Spencer, J., and Luparello, C. (2012) Cytotoxic effects of Jay Amin hydroxamic acid (JAHA), a ferrocene-based class I histone deacetylase inhibitor, on triple-negative MDA-MB231 breast cancer cells Chem. Res. Toxicol. 25, 2608– 2616 DOI: 10.1021/tx300376h
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    Howe, E. N., Cochrane, D. R., and Richer, J. K. (2011) Targets of miR-200c mediate suppression of cell motility and anoikis resistance Breast Cancer Res. 13, R45 DOI: 10.1186/bcr2867
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    Targets of miR-200c mediate suppression of cell motility and anoikis resistance
    Howe, Erin N.; Cochrane, Dawn R.; Richer, Jennifer K.
    Breast Cancer Research (2011), 13 (), R45CODEN: BRCRFS; ISSN:1465-542X. (BioMed Central Ltd.)
    Introduction: miR-200c and other members of the miR-200 family promote epithelial identity by directly targeting ZEB1 and ZEB2, which repress E-cadherin and other genes involved in polarity. Loss of miR-200c is often obsd. in carcinoma cells that have undergone epithelial to mesenchymal transition (EMT). Restoration of miR-200c to such cells leads to a redn. in stem cell-like characteristics, reduced migration and invasion, and increased sensitivity to taxanes. Here we investigate the functional role of novel targets of miR-200c in the aggressive behavior of breast and endometrial cancer cells. Methods: Putative target genes of miR-200c identified by microarray profiling were validated as direct targets using dual luciferase reporter assays. Following restoration of miR-200c to triple neg. breast cancer and type 2 endometrial cancer cell lines that had undergone EMT, levels of endogenous target mRNA and resp. protein products were measured. Migration and sensitivity to anoikis were detd. using wound healing assays or cell-death ELISAs and viability assays resp. Results: We found that restoration of miR-200c suppresses anoikis resistance, a novel function for this influential miRNA. We identified novel targets of miR-200c, including genes encoding fibronectin 1 (FN1), moesin (MSN), neurotrophic tyrosine receptor kinase type 2 (NTRK2 or TrkB), leptin receptor (LEPR), and Rho GTPase activating protein 19 (ARHGAP19). These targets all encode proteins normally expressed in cells of mesenchymal or neuronal origin; however, in carcinoma cells that lack miR-200c they become aberrantly expressed and contribute to the EMT phenotype and aggressive behavior. We showed that these targets are inhibited upon restoration of miR-200c to aggressive breast and endometrial cancer cells. We demonstrated that inhibition of MSN and/or FN1 is sufficient to mediate the ability of miR-200c to suppress cell migration. Lastly, we showed that targeting of TrkB mediates the ability of miR-200c to restore anoikis sensitivity. Conclusions: Thus, miR-200c maintains the epithelial phenotype not only by targeting ZEB1/2, which usually facilitates restoration of E-cadherin expression, but also by actively repressing a program of mesenchymal and neuronal genes involved in cell motility and anoikis resistance.
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    Kim, M. S., Lee, W. S., Jeong, J., Kim, S. J., and Jin, W. (2015) Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer Oncotarget 6, 40158– 40171 DOI: 10.18632/oncotarget.5522
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    Fujita, K., Tatsumi, K., Kondoh, E., Chigusa, Y., Mogami, H., Fujii, T., Yura, S., Kakui, K., and Konishi, I. (2011) Differential expression and the anti-apoptotic effect of human placental neurotrophins and their receptors Placenta 32, 737– 744 DOI: 10.1016/j.placenta.2011.07.001
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    Yang, J. L., Lin, Y. T., Chuang, P. C., Bohr, V. A., and Mattson, M. P. (2014) BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1 NeuroMol. Med. 16, 161– 174 DOI: 10.1007/s12017-013-8270-x
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    29
    BDNF and Exercise Enhance Neuronal DNA Repair by Stimulating CREB-Mediated Production of Apurinic/Apyrimidinic Endonuclease 1
    Yang, Jenq-Lin; Lin, Yu-Ting; Chuang, Pei-Chin; Bohr, Vilhelm A.; Mattson, Mark P.
    NeuroMolecular Medicine (2014), 16 (1), 161-174CODEN: NMEEAN; ISSN:1535-1084. (Humana Press Inc.)
    Brain-derived neurotrophic factor (BDNF) promotes the survival and growth of neurons during brain development and mediates activity-dependent synaptic plasticity and assocd. learning and memory in the adult. BDNF levels are reduced in brain regions affected in Alzheimer's, Parkinson's, and Huntington's diseases, and elevation of BDNF levels can ameliorate neuronal dysfunction and degeneration in exptl. models of these diseases. Because neurons accumulate oxidative lesions in their DNA during normal activity and in neurodegenerative disorders, we detd. whether and how BDNF affects the ability of neurons to cope with oxidative DNA damage. We found that BDNF protects cerebral cortical neurons against oxidative DNA damage-induced death by a mechanism involving enhanced DNA repair. BDNF stimulates DNA repair by activating cAMP response element-binding protein (CREB), which, in turn, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair pathway. Suppression of either APE1 or TrkB by RNA interference abolishes the ability of BDNF to protect neurons against oxidized DNA damage-induced death. The ability of BDNF to activate CREB and upregulate APE1 expression is abolished by shRNA of TrkB as well as inhibitors of TrkB, PI3 kinase, and Akt kinase. Voluntary running wheel exercise significantly increases levels of BDNF, activates CREB, and upregulates APE1 in the cerebral cortex and hippocampus of mice, suggesting a novel mechanism whereby exercise may protect neurons from oxidative DNA damage. Our findings reveal a previously unknown ability of BDNF to enhance DNA repair by inducing the expression of the DNA repair enzyme APE1.
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    Zhang, D., Tang, B., Xie, X., Xiao, Y. F., Yang, S. M., and Zhang, J. W. (2015) The interplay between DNA repair and autophagy in cancer therapy Cancer Biol. Ther. 16, 1005– 1013 DOI: 10.1080/15384047.2015.1046022
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    The interplay between DNA repair and autophagy in cancer therapy
    Zhang, Dan; Tang, Bo; Xie, Xia; Xiao, Yu-Feng; Yang, Shi-Ming; Zhang, Jian-Wei
    Cancer Biology & Therapy (2015), 16 (7), 1005-1013CODEN: CBTAAO; ISSN:1555-8576. (Taylor & Francis Ltd.)
    DNA is the prime target of anticancer treatments. DNA damage triggers a series of signaling cascades promoting cellular survival, including DNA repair, cell cycle arrest, and autophagy. The elevated basal and/or stressful levels of both DNA repair and autophagy obsd. in tumor cells, in contrast to normal cells, have been identified as the most important drug-responsive programs that impact the outcome of anticancer therapy. The exact relationship between DNA repair and autophagy in cancer cells remains unclear. On one hand, autophagy has been shown to regulate some of the DNA repair proteins after DNA damage by maintaining the balance between their synthesis, stabilization, and degrdn. One the other hand, some evidence has demonstrated that some DNA repair mol. have a crucial role in the initiation of autophagy. In this review, we mainly discuss the interplay between DNA repair and autophagy in anticancer therapy and expect to enlighten some effective strategies for cancer treatment.
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    Lee, J. H., Choy, M. L., Ngo, L., Foster, S. S., and Marks, P. A. (2010) Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair Proc. Natl. Acad. Sci. U. S. A. 107, 14639– 14644 DOI: 10.1073/pnas.1008522107
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    Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair
    Lee, J.-H.; Choy, M. L.; Ngo, L.; Foster, S. S.; Marks, Paul A.
    Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (33), 14639-14644, S14639/1-S14639/2CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, we show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (γH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-h culture of cells with vorinostat, and reculture without the HDACi, γH2AX was undetectable by 2 h in normal cells, while persisting in transformed cells for the duration of culture. Further, we found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is assocd. with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concns. that cause little or no normal cell death.
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  32. 32
    Jeong, W., Bae, S. H., Toledano, M. B., and Rhee, S. G. (2012) Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression Free Radical Biol. Med. 53, 447– 456 DOI: 10.1016/j.freeradbiomed.2012.05.020
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    Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression
    Jeong, Woojin; Bae, Soo Han; Toledano, Michel B.; Rhee, Sue Goo
    Free Radical Biology & Medicine (2012), 53 (3), 447-456CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
    A review. Peroxiredoxins (Prxs) constitute a family of peroxidases in which Cys serves as the primary site of oxidn. during the redn. of peroxides. Members of the 2-Cys Prx subfamily of Prxs (Prx I to IV in mammals) are inactivated via hyperoxidn. of the active site Cys residue to sulfinic acid (Cys-SO2H) during catalysis and are reactivated via an ATP-consuming reaction catalyzed by sulfiredoxin (Srx). This reversible hyperoxidn. reaction has been proposed to protect H2O2 signaling mols. from premature removal by 2-Cys Prxs or to up-regulate the chaperone function of these enzymes. In addn. to its sulfinic acid reductase activity, Srx catalyzes the removal of glutathione (deglutathionylation) from modified proteins. The physiol. relevance of both the reversible hyperoxidn. of 2-Cys Prxs and the deglutathionylation catalyzed by Srx remains unclear. Recent findings have revealed that Srx expression is induced in mammalian cells under a variety of conditions, such as in metabolically stimulated pancreatic β-cells, in immunostimulated macrophages, in neuronal cells engaged in synaptic communication, in lung cells exposed to hyperoxia or cigarette smoke, in hepatocytes of EtOH-fed animals, and in several types of cells exposed to chemopreventive agents. Such induction of Srx in mammalian cells is regulated at the transcriptional level, predominantly via activator protein-1 and/or nuclear factor erythroid 2-related factor 2. Srx expression is also regulated at the translational level in Saccharomyces cerevisiae.
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    Avval, F. Z. and Holmgren, A. (2009) Molecular mechanisms of thioredoxin and glutaredoxin as hydrogen donors for Mammalian s phase ribonucleotide reductase J. Biol. Chem. 284, 8233– 8240 DOI: 10.1074/jbc.M809338200
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    Butinar, M., Prebanda, M. T., Rajković, J., Jerič, B., Stoka, V., Peters, C., Reinheckel, T., Krüger, A., Turk, V., Turk, B., and Vasiljeva, O. (2014) Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model Oncogene 33, 3392– 3400 DOI: 10.1038/onc.2013.314
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    Bose, P., Dai, Y., and Grant, S. (2014) Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights Pharmacol. Ther. 143, 323– 336 DOI: 10.1016/j.pharmthera.2014.04.004
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    Histone deacetylase inhibitor (HDACI) mechanisms of action: Emerging insights
    Bose, Prithviraj; Dai, Yun; Grant, Steven
    Pharmacology & Therapeutics (2014), 143 (3), 323-336CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)
    A review. Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addn. to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clin. studies. In recent years, addnl. mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, crit. to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clin. potential, the clin. use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.
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  36. 36
    Gatei, M., Kijas, A. W., Biard, D., Dörk, T., and Lavin, M. F. (2014) RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress Hum. Mol. Genet. 23, 4232– 4248 DOI: 10.1093/hmg/ddu141
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    RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress
    Gatei, Magtouf; Kijas, Amanda W.; Biard, Denis; Doerk, Thilo; Lavin, Martin F.
    Human Molecular Genetics (2014), 23 (16), 4232-4248CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
    The MRE11/RAD50/NBN (MRN) complex plays a key role in detecting DNA double-strand breaks, recruiting and activating ataxia-telangiectasia mutated and in processing the breaks. Members of this complex also act as adaptor mols. for downstream signaling to the cell cycle and other cellular processes. Somewhat more controversial are the results to support a role for MRN in the ataxia-telangiectasia and Rad3-related (ATR) activation and signaling. We provide evidence that RAD50 is required for ATR activation in mammalian cells in response to DNA replication stress. It is in turn phosphorylated at a specific site (S635) by ATR, which is required for ATR signaling through Chk1 and other downstream substrates. We find that RAD50 phosphorylation is essential for DNA replication restart by promoting loading of cohesin at these sites. We also demonstrate that replication stress-induced RAD50 phosphorylation is functionally significant for cell survival and cell cycle checkpoint activation. These results highlight the importance of the adaptor role for a member of the MRN complex in all aspects of the response to DNA replication stress.
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    Brezniceanu, M. L., Völp, K., Bösser, S., Solbach, C., Lichter, P., Joos, S., and Zörnig, M. (2003) HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma FASEB J. 17, 1295– 1297 DOI: 10.1096/fj.02-0621fje
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    Chang, B. P., Wang, D. S., Xing, J. W., Yang, S. H., Chu, Q., and Yu, S. Y. (2014) miR-200c inhibits metastasis of breast cancer cells by targeting HMGB1 J. Huazhong Univ. Sci. Technol., Med. Sci. 34, 201– 206 DOI: 10.1007/s11596-014-1259-3
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    Krynetskaia, N. F., Phadke, M. S., Jadhav, S. H., and Krynetskiy, E. Y. (2009) Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage Mol. Cancer Ther. 8, 864– 872 DOI: 10.1158/1535-7163.MCT-08-0695
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    39
    Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage
    Krynetskaia, Natalia F.; Phadke, Manali S.; Jadhav, Sachin H.; Krynetskiy, Evgeny Y.
    Molecular Cancer Therapeutics (2009), 8 (4), 864-872CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
    The identification of new mol. components of the DNA damage signaling cascade opens novel avenues to enhance the efficacy of chemotherapeutic drugs. High-mobility group protein 1 (HMGB1) is a DNA damage sensor responsive to the incorporation of nonnatural nucleosides into DNA; several nuclear and cytosolic proteins are functionally integrated with HMGB1 in the context of DNA damage response. The functional role of HMGB1 and HMGB1-assocd. proteins (high-mobility group protein B2, HMGB2; glyceraldehyde-3-phosphate dehydrogenase, GAPDH; protein disulfide isomerase family A member 3, PDIA3; and heat shock 70 kDa protein 8, HSPA8) in DNA damage response was assessed in human carcinoma cells A549 and UO31 by transient knockdown with short interfering RNAs. Using the cell proliferation assay, we found that knockdown of HMGB1-assocd. proteins resulted in 8-fold to 50-fold decreased chemosensitivity of A549 cells to cytarabine. Western blot anal. and immunofluorescent microscopy were used to evaluate genotoxic stress markers in knocked-down cancer cells after 24 to 72 h of incubation with 1 μmol/L of cytarabine. Our results dissect the roles of HMGB1-assocd. proteins in DNA damage response: HMGB1 and HMGB2 facilitate p53 phosphorylation after exposure to genotoxic stress, and PDIA3 has been found essential for H2AX phosphorylation (no γ-H2AX accumulated after 24-72 h of incubation with 1 μmol/L of cytarabine in PDIA3 knockdown cells). We conclude that phosphorylation of p53 and phosphorylation of H2AX occur in two distinct branches of the DNA damage response. These findings identify new mol. components of the DNA damage signaling cascade and provide novel promising targets for chemotherapeutic intervention.
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    Tsai, H. Y., Yang, Y. F., Wu, A. T., Yang, C. J., Liu, Y. P., Jan, Y. H., Lee, C. H., Hsiao, Y. W., Yeh, C. T., Shen, C. N., Lu, P. J., Huang, M. S., and Hsiao, M. (2013) Endoplasmic reticulum ribosome-binding protein 1 (RRBP1) overexpression is frequently found in lung cancer patients and alleviates intracellular stress-induced apoptosis through the enhancement of GRP78 Oncogene 32, 4921– 4931 DOI: 10.1038/onc.2012.514
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    Kelland, L. R., Smith, V., Valenti, M., Patterson, L., Clarke, P. A., Detre, S., End, D., Howes, A. J., Dowsett, M., Workman, P., and Johnston, S. R. (2001) Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer Clin. Cancer Res. 7, 3544– 3550
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    Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer
    Kelland, Lloyd R.; Smith, Vicki; Valenti, Melanie; Patterson, Lisa; Clarke, Paul A.; Detre, Simone; End, Dave; Howes, Angela J.; Dowsett, Mitch; Workman, Paul; Johnston, Stephen R. D.
    Clinical Cancer Research (2001), 7 (11), 3544-3550CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
    Antitumor and pharmacodynamic studies were performed in MCF-7 human breast cancer cells and companion xenografts with the farnesyl protein transferase inhibitor, R115777, presently undergoing Phase II clin. trials, including in breast cancer. R115777 inhibited the growth of MCF-7 cells in vitro with an IC50 of 0.31 ± 0.25 μM. Exposure of MCF-7 cells to increasing concns. of R115777 for 24 h resulted in the inhibition of protein farnesylation, as indicated by the appearance of prelamin A at concns. >1 μM. After continuous exposure to 2 μM R115777, prelamin A levels peaked at 2 h post drug exposure and remained high for up to 72 h. R115777 administered orally twice daily for 10 consecutive days to mice bearing established s.c. MCF-7 xenografts induced tumor inhibition at a dose of 25 mg/kg [percentage of treated vs. control (% T/C) = 63% at day 21]. Greater inhibition was obsd. at doses of 50 mg/kg (% T/C at day 21 = 38%) or 100 mg/kg (% T/C at day 21 = 43%). The antitumor effect appeared to be mainly cytostatic with little evidence of tumor shrinkage to less than the starting vol. Tumor response correlated with an increase in the appearance of prelamin A, but no changes in the prenylation of lamin B, heat-shock protein 40, or N-Ras were detectable. In addn., significant increases in apoptotic index and p21WAF1/CIP1 expression were obsd., concomitant with a decrease in proliferation as measured by Ki-67 staining. An increase in prelamin A was also obsd. in peripheral blood lymphocytes in a breast cancer patient who responded to R115777. These data show that R115777 possesses preclin. antitumor activity against human breast cancer and that the appearance of prelamin A may provide a sensitive and convenient pharmacodynamic marker of inhibition of prenylation and(or) response.
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  42. 42
    Sieprath, T., Corne, T. D., Nooteboom, M., Grootaert, C., Rajkovic, A., Buysschaert, B., Robijns, J., Broers, J. L., Ramaekers, F. C., Koopman, W. J., Willems, P. H., and De Vos, W. H. (2015) Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates Nucleus 6, 236– 246 DOI: 10.1080/19491034.2015.1050568
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    42
    Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates
    Sieprath, Tom; Corne, Tobias D. J.; Nooteboom, Marco; Grootaert, Charlotte; Rajkovic, Andreja; Buysschaert, Benjamin; Robijns, Joke; Broers, Jos L. V.; Ramaekers, Frans C. S.; Koopman, Werner J. H.; Willems, Peter H. G. M.; De Vos, Winnok H.
    Nucleus (Philadelphia, PA, United States) (2015), 6 (3), 236-246CODEN: NPPUBC; ISSN:1949-1042. (Taylor & Francis, Inc.)
    The cell nucleus is structurally and functionally organized by lamins, intermediate filament proteins that form the nuclear lamina. Point mutations in genes that encode a specific subset of lamins, the A-type lamins, cause a spectrum of diseases termed laminopathies. Recent evidence points to a role for A-type lamins in intracellular redox homeostasis. To det. whether lamin A/C depletion and prelamin A accumulation differentially induce oxidative stress, we have performed a quant. microscopy-based anal. of reactive oxygen species (ROS) levels and mitochondrial membrane potential (Δψm) in human fibroblasts subjected to sustained siRNA-mediated knockdown of LMNA and ZMPSTE24, resp. We measured a highly significant increase in basal ROS levels and an even more prominent rise of induced ROS levels in lamin A/C depleted cells, eventually resulting in Δψm hyperpolarization and apoptosis. Depletion of ZMPSTE24 on the other hand, triggered a senescence pathway that was assocd. with moderately increased ROS levels and a transient Δψm depolarization. Both knockdowns were accompanied by an upregulation of several ROS detoxifying enzymes. Taken together, our data suggest that both persistent prelamin A accumulation and lamin A/C depletion elevate ROS levels, but to a different extent and with different effects on cell fate. This may contribute to the variety of disease phenotypes witnessed in laminopathies.
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    Rowinsky, E. K., Windle, J. J., and Von Hoff, D. D. (1999) Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development J. Clin. Oncol. 17, 3631– 3652 DOI: 10.1200/JCO.1999.17.11.3631
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    Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development
    Rowinsky, Eric K.; Windle, Jolene J.; Von Hoff, Daniel D.
    Journal of Clinical Oncology (1999), 17 (11), 3631-3652CODEN: JCONDN; ISSN:0732-183X. (Lippincott Williams & Wilkins)
    A review with 175 refs. Ras proteins are guanine nucleotide-binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approx. 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first-and most crit.-modification is the addn. of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biol. active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clin. evaluations of FTase inhibitors to det. the feasibility of administering them on dose schedules like those that portend optimal therapeutic indexes in preclin. studies. Because of the unique biol. aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.
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    Körner, C., Keklikoglou, I., Bender, C., Wörner, A., Münstermann, E., and Wiemann, S. (2013) MicroRNA-31 sensitizes human breast cells to apoptosis by direct targeting of protein kinase C epsilon (PKC epsilon) J. Biol. Chem. 288, 8750– 8761 DOI: 10.1074/jbc.M112.414128
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    Girardot, V., Rabilloud, T., Yoshida, M., Beppu, T., Lawrence, J. J., and Khochbin, S. (1994) Relationship between core histone acetylation and histone H1(0) gene activity Eur. J. Biochem. 224, 885– 892 DOI: 10.1111/j.1432-1033.1994.00885.x
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    Relationship between core histone acetylation and histone H10 gene activity
    Girardot, Valerie; Rabilloud, Thierry; Yoshida, Minoru; Beppu, Teruhiko; Lawrence, Jean-Jacques; Khochbin, Saadi
    European Journal of Biochemistry (1994), 224 (3), 885-92CODEN: EJBCAI; ISSN:0014-2956.
    In this study we show a striking correlation between histone H10 gene expression and histone acetylation. Trichostatin A, a highly specific inhibitor of histone deacetylase, efficiently induces H10 gene expression. Moreover, using a cell line sensitive to trichostatin A (FM3A) and a derived cell line selected for its resistance to this inhibitor (TR303), it is shown that the level of H10 gene expression is related to the extent of chromatin acetylation. After showing the S-phase-dependent activation of H10 gene expression, we demonstrate that hyperacetylation has a dominant effect on H10 gene expression, since it enhances the expression of the gene independent of the position of cells in the cell cycle. This response to deacetylase inhibitors is specific to H10, since it is not shared by other cell-cycle-dependent histone genes (h1 and H4). Finally, by transfection of trichostatin-A-resistant and trichostatin-A-sensitive cells with a plasmid contg. a H10 promoter, we show that the exogenous H10 promoter is also highly sensitive to trichostatin A treatment and that activation of transcription follows exactly the same pattern as activation of the endogenous gene. Histone acetylation may be used to modulate H10 gene activity and offers insight into a possible mechanism in which the developmentally regulated chromatin acetylation acts to potentiate H10 gene expression.
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    Kostova, N. N., Srebreva, L. N., Milev, A. D., Bogdanova, O. G., Rundquist, I., Lindner, H. H., and Markov, D. V. (2005) Immunohistochemical demonstration of histone H1(0) in human breast carcinoma Histochem. Cell Biol. 124, 435– 443 DOI: 10.1007/s00418-005-0052-6
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    Immunohistochemical demonstration of histone H10 in human breast carcinoma
    Kostova, Nora N.; Srebreva, Ljuba N.; Milev, Angel D.; Bogdanova, Olga G.; Rundquist, Ingemar; Lindner, Herbert H.; Markov, Dimiter V.
    Histochemistry and Cell Biology (2005), 124 (5), 435-443CODEN: HCBIFP; ISSN:0948-6143. (Springer)
    Histone H10 is a linker histone subvariant present in tissues of low proliferation rate. It is supposed to participate in the expression and maintenance of the terminal differentiation phenotype. The aim of this work was to study histone H10 distribution in human breast carcinoma and its relationship with the processes of proliferation and differentiation. Most of the cells in carcinomas of moderate and high level of differentiation expressed histone H10 including cells invading connective and adipose tissues. In low differentiated tumors, the no. of H10 expressing cells was considerably lower. Staining of myoepithelial cells, when seen, and of stromal fibroblasts was variable. The metastatic malignant cells in the lymph nodes also accumulated H10 but lymphocytes were always neg. All immunopos. malignant cells exhibited signs of polymorphism. Double H10/Ki-67 staining showed that the growth fraction in more differentiated tumors belonged to the H10-pos. cells, while in poorly differentiated carcinomas it also included a cell subpopulation not expressing H10. If expressed, p27Kip1 was always found in H10-pos. cells. These findings are inconsistent with the widespread view that histone H10 is expressed only in terminally differentiated cells. Rather, they suggest that the protein is expressed in cells in a prolonged intermitotic period irresp. of their level of differentiation. Double H10/Ki-67 immunostaining could be a useful tool in studying the growth fraction in tumors.
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    Varisli, L., Gonen-Korkmaz, C., Debelec-Butuner, B., Erbaykent-Tepedelen, B., Muhammed, H. S., Bogurcu, N., Saatcioglu, F., and Korkmaz, K. S. (2011) Ubiquitously expressed hematological and neurological expressed 1 downregulates Akt-mediated GSK3β signaling, and its knockdown results in deregulated G2/M transition in prostate cells DNA Cell Biol. 30, 419– 429 DOI: 10.1089/dna.2010.1128
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    Davis, T. A., Loos, B., and Engelbrecht, A. M. (2014) AHNAK: the giant jack of all trades Cell. Signalling 26, 2683– 2693 DOI: 10.1016/j.cellsig.2014.08.017
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    AHNAK: The giant jack of all trades
    Davis, T. A.; Loos, B.; Engelbrecht, A.-M.
    Cellular Signalling (2014), 26 (12), 2683-2693CODEN: CESIEY; ISSN:0898-6568. (Elsevier)
    A review. The nucleoprotein AHNAK is an unusual and somewhat mysterious scaffolding protein characterized by its large size of approx. 700 kDa. Several aspects of this protein remain uncertain, including its exact mol. function and regulation on both the gene and protein levels. Various studies have attempted to annotate AHNAK and, notably, protein interaction and expression analyses have contributed greatly to our current understanding of the protein. The implicated biol. processes are, however, very diverse, ranging from a role in the formation of the blood-brain barrier, cell architecture and migration, to the regulation of cardiac calcium channels and muscle membrane repair. In addn., recent evidence suggests that AHNAK might be yet another accomplice in the development of tumor metastasis. This review will discuss the different functional roles of AHNAK, highlighting recent advancements that have added foundation to the proposed roles while identifying ties between them. Implications for related fields of research are noted and suggestions for future research that will assist in unravelling the function of AHNAK are offered.
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    Caruso, J. A. and Stemmer, P. M. (2011) Proteomic profiling of lipid rafts in a human breast cancer model of tumorigenic progression Clin. Exp. Metastasis 28, 529– 540 DOI: 10.1007/s10585-011-9389-5
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    Proteomic profiling of lipid rafts in a human breast cancer model of tumorigenic progression
    Caruso, Joseph A.; Stemmer, Paul M.
    Clinical & Experimental Metastasis (2011), 28 (6), 529-540CODEN: CEXMD2; ISSN:0262-0898. (Springer)
    Tumor biomarkers assist in the early detection of cancer, act as therapeutic targets for intervention, and function as diagnostic indicators for the evaluation of therapeutic responses. To identify novel human breast cancer biomarkers, we have analyzed the protein content of lipid rafts isolated from a series of human mammary epithelial cell lines with increasing tumorigenic potential. Since lipid rafts function as platforms for protein interaction crit. to several biol. processes, we hypothesized that the abundance of proteins assocd. with proliferation, invasion and metastasis would be dysregulated in highly transformed cells. For this purpose, the MCF10A epithelial lineage, which include benign MCF10A cells, premalignant AT and TG3B cells, and malignant CA1a tumor cells, was utilized. Detergent-resistant membranes were isolated from each line and proteins were identified and relatively quantitated using iTRAQ reagents and tandem mass spectrometry. 57 Proteins were identified, and 1667 peptide identifications, mapping to 49 proteins, contained sufficient information for semi-quant. anal. When comparing malignant to benign cells, we obsd. consistent alterations in groups of proteins, such as a 5.7-fold av. decrease in G protein content (n = 5), 2.7-fold decrease in glycosylphosphatidylinositol-linked proteins (n = 7) and 3.3-fold increase in intermediate filaments (n = 9). Several of the identified proteins, including caveolin-1, filamin A, keratins 5, 6 and 17, and vimentin, are bona fide or candidate biomarkers in clin. studies, underscoring the usefulness of the MCF10A series as a model to better understand the biol. mechanisms underlying cancer progression.
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  50. 50
    Yoshimaru, T., Ono, M., Bando, Y., Chen, Y. A., Mizuguchi, K., Shima, H., Komatsu, M., Imoto, I., Izumi, K., Honda, J., Miyoshi, Y., Sasa, M., and Katagiri, T. (2017) A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells Nat. Commun. 8, 15427 DOI: 10.1038/ncomms15427
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    50
    A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells
    Yoshimaru, Tetsuro; Ono, Masaya; Bando, Yoshimi; Chen, Yi-An; Mizuguchi, Kenji; Shima, Hiroshi; Komatsu, Masato; Imoto, Issei; Izumi, Keisuke; Honda, Junko; Miyoshi, Yasuo; Sasa, Mitsunori; Katagiri, Toyomasa
    Nature Communications (2017), 8 (), 15427CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    Approx. 70% of breast cancer cells express estrogen receptor alpha (ERα). Previous studies have shown that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex has a crucial role in these cells. However, it remains unclear how BIG3 regulates the suppressive activity of PHB2. Here we demonstrate that BIG3 functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and the α isoform of the catalytic subunit of protein phosphatase 1 (PP1Cα), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and -S1208 serves to enhance PP1Cα activity, resulting in E2/ERα signalling activation via PHB2 inactivation due to PHB2-S39 dephosphorylation. Furthermore, an anal. of independent cohorts of ERα-pos. breast cancers patients reveal that both BIG3 overexpression and PHB2-S39 dephosphorylation are strongly assocd. with poor prognosis. This is the first demonstration of the mechanism of E2/ERα signalling activation via the BIG3-PKA-PP1Cα tri-complex in breast cancer cells.
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  51. 51
    Paget, J. A., Restall, I. J., Daneshmand, M., Mersereau, J. A., Simard, M. A., Parolin, D. A., Lavictoire, S. J., Amin, M. S., Islam, S., and Lorimer, I. A. (2012) Repression of cancer cell senescence by PKCι Oncogene 31, 3584– 3596 DOI: 10.1038/onc.2011.524
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    Paul, A., Gunewardena, S., Stecklein, S. R., Saha, B., Parelkar, N., Danley, M., Rajendran, G., Home, P., Ray, S., Jokar, I., Vielhauer, G. A., Jensen, R. A., Tawfik, O., and Paul, S. (2014) PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis Cell Death Differ. 21, 1469– 1481 DOI: 10.1038/cdd.2014.62
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    52
    PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis
    Paul, A.; Gunewardena, S.; Stecklein, S. R.; Saha, B.; Parelkar, N.; Danley, M.; Rajendran, G.; Home, P.; Ray, S.; Jokar, I.; Vielhauer, G. A.; Jensen, R. A.; Tawfik, O.; Paul, S.
    Cell Death & Differentiation (2014), 21 (9), 1469-1481CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)
    Triple-neg. breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional anal. in exptl. mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly assocd. with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We obsd. that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a therapeutic option for breast cancer, including the TNBC subtype.
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  53. 53
    Vaysse, C., Philippe, C., Martineau, Y., Quelen, C., Hieblot, C., Renaud, C., Nicaise, Y., Desquesnes, A., Pannese, M., Filleron, T., Escourrou, G., Lawson, M., Rintoul, R. C., Delisle, M. B., Pyronnet, S., Brousset, P., Prats, H., and Touriol, C. (2015) Key contribution of eIF4H-mediated translational control in tumor promotion Oncotarget 6, 39924– 39940 DOI: 10.18632/oncotarget.5442
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    Hong, S. M., Park, C. W., Kim, S. W., Nam, Y. J., Yu, J. H., Shin, J. H., Yun, C. H., Im, S. H., Kim, K. T., Sung, Y. C., and Choi, K. Y. (2016) NAMPT suppresses glucose deprivation-induced oxidative stress by increasing NADPH levels in breast cancer Oncogene 35, 3544– 3554 DOI: 10.1038/onc.2015.415
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    Liu, X., Daskal, I., and Kwok, S. C. (2003) Effects of PTX1 expression on growth and tumorigenicity of the prostate cancer cell line PC-3 DNA Cell Biol. 22, 469– 474 DOI: 10.1089/104454903322247343
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    Browne, B. C., Hochgräfe, F., Wu, J., Millar, E. K., Barraclough, J., Stone, A., McCloy, R. A., Lee, C. S., Roberts, C., Ali, N. A., Boulghourjian, A., Schmich, F., Linding, R., Farrow, L., Gee, J. M., Nicholson, R. I., O’Toole, S. A., Sutherland, R. L., Musgrove, E. A., Butt, A. J., and Daly, R. J. (2013) Global characterization of signalling networks associated with tamoxifen resistance in breast cancer FEBS J. 280, 5237– 5257 DOI: 10.1111/febs.12441
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    Wang, W. H., Childress, M. O., and Geahlen, R. L. (2014) Syk interacts with and phosphorylates nucleolin to stabilize Bcl-x(L) mRNA and promote cell survival Mol. Cell. Biol. 34, 3788– 3799 DOI: 10.1128/MCB.00937-14
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    57
    Syk interacts with and phosphorylates nucleolin to stabilize Bcl-xL mRNA and promote cell survival
    Wang, Wen-Horng; Childress, Michael O.; Geahlena, Robert L.
    Molecular and Cellular Biology (2014), 34 (20), 3788-3799, 13 pp.CODEN: MCEBD4; ISSN:1098-5549. (American Society for Microbiology)
    The Syk protein tyrosine kinase, a well-characterized regulator of immune cell function, plays an increasingly recognized role in tumorigenesis as a promoter of cell survival in both hematol. and nonhematol. malignancies. We show here that the expression of Syk in MCF7 or MDA-MB-231 breast cancer cells or in DG75 B-lymphoma cells protects cells from apoptosis induced by oxidative or genotoxic stress by stabilizing the mRNA for Bcl-xL, an antiapoptotic protein. Syk binds robustly to nucleolin and phosphorylates it on tyrosine, enhancing its ability to bind the Bcl-xL mRNA. Consequently, reducing the level of nucleolin by RNA interference attenuates the ability of Syk to protect cells from stress-induced cell death.
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  58. 58
    Christensen, L. L., Holm, A., Rantala, J., Kallioniemi, O., Rasmussen, M. H., Ostenfeld, M. S., Dagnaes-Hansen, F., Øster, B., Schepeler, T., Tobiasen, H., Thorsen, K., Sieber, O. M., Gibbs, P., Lamy, P., Hansen, T. F., Jakobsen, A., Riising, E. M., Helin, K., Lubinski, J., Hagemann-Madsen, R., Laurberg, S., Ørntoft, T. F., and Andersen, C. L. (2014) Functional screening identifies miRNAs influencing apoptosis and proliferation in colorectal cancer PLoS One 9, e96767 DOI: 10.1371/journal.pone.0096767
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    Nakakido, M., Tamura, K., Chung, S., Ueda, K., Fujii, R., Kiyotani, K., and Nakamura, Y. (2016) Phosphatidylinositol glycan anchor biosynthesis, class X containing complex promotes cancer cell proliferation through suppression of EHD2 and ZIC1, putative tumor suppressors Int. J. Oncol. 49, 868– 876 DOI: 10.3892/ijo.2016.3607
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    59
    Phosphatidylinositol glycan anchor biosynthesis, class X containing complex promotes cancer cell proliferation through suppression of EHD2 and ZIC1, putative tumor suppressors
    Nakakido, Makoto; Tamura, Kenji; Chung, Suyoun; Ueda, Koji; Fujii, Risa; Kiyotani, Kazuma; Nakamura, Yusuke
    International Journal of Oncology (2016), 49 (3), 868-876CODEN: IJONES; ISSN:1791-2423. (Spandidos Publications Ltd.)
    We identified phosphatidylinositol glycan anchor biosynthesis, class X (PIGX), which plays a crit. role in the biosynthetic pathway of glycosylphosphatidylinositol (GPI)-anchor motif, to be upregulated highly and frequently in breast cancer cells. Knockdown of PIGX as well as reticulocalbin 1 (RCN1) and reticulocalbin 2 (RCN2), which we found to interact with PIGX and was indicated to regulate calcium-dependent activities, significantly suppressed the growth of breast cancer cells. We also identified PIGX to be a core protein in an RCN1/PIGX/RCN2 complex. Microarray anal. revealed that the expression of two putative tumor suppressor genes, Zic family member 1 (ZIC1) and EH-domain contg. 2 (EHD2), were upregulated commonly in cells in which PIGX, RCN1, or RCN2 was knocked down, suggesting that this RCN1/PIGX/RCN2 complex could neg. regulate the expression of these two genes and thereby contribute to human breast carcinogenesis. Our results imply that PIGX may be a good candidate mol. for development of novel anticancer drugs for breast cancer.
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  60. 60
    Sareen, D., Darjatmoko, S. R., Albert, D. M., and Polans, A. S. (2007) Mitochondria, calcium, and calpain are key mediators of resveratrol-induced apoptosis in breast cancer Mol. Pharmacol. 72, 1466– 1475 DOI: 10.1124/mol.107.039040
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    Gong, B., Hu, H., Chen, J., Cao, S., Yu, J., Xue, J., Chen, F., Cai, Y., He, H., and Zhang, L. (2013) Caprin-1 is a novel microRNA-223 target for regulating the proliferation and invasion of human breast cancer cells Biomed. Pharmacother. 67, 629– 636 DOI: 10.1016/j.biopha.2013.06.006
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    61
    Caprin-1 is a novel microRNA-223 target for regulating the proliferation and invasion of human breast cancer cells
    Gong, Bo; Hu, Heyu; Chen, Jia; Cao, Shuang; Yu, Jing; Xue, Jianxiang; Chen, Fuhua; Cai, Ye; He, Hong; Zhang, Lei
    Biomedicine & Pharmacotherapy (2013), 67 (7), 629-636CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
    MicroRNAs (miRNAs) are 21-22 nucleotides regulatory small non-coding RNAs that inhibit gene expression by binding to complementary sequences esp. the 3' untranslated region (3'UTR) of mRNA. One miRNA can target many mRNAs, leading to a complex metabolic network. Previous studies have shown that miRNA-223 regulates migration and invasion of tumor cells and targets cytoplasmic activation/proliferation-assocd. protein-1 (Caprin-1). In the present study, we detected the expression of miRNA-223 and Caprin-1 in MCF-7, T-47D and MDA-MB-231 cancer cell lines, and MCF-10A normal breast cell line, and analyzed the role of miRNA-223 in Caprin-1-induced proliferation and invasion of human breast cancer cells. We found that miRNA-223 expression levels are significantly lower in MCF-7, T-47D and MDA-MB-231 cancer cells than in MCF-10A normal breast cells, while Caprin-1 expression is higher in cancer cells than in normal breast cells. The most malignant cancer cell line MDA-MB-231 has the lowest expression of miR-223, but the highest expression of Caprin-1. Further, we found that miR-223 targets the 3'UTR of Caprin-1 miRNA and down-regulates the expression of Caprin-1. We also found that over-expression of Caprin-1 can promote the proliferation and the invasion of breast cancer cells, but miRNA-223 can inhibit the proliferation and the invasion. miRNA-223-induced inhibition can be reversed by ectopic over-expression of Caprin-1. These findings suggest that miR-223 may suppress the proliferation and invasion of cancer cells by directly targeting Caprin-1. Our study also indicates that expression levels of miR-223 and Caprin-1 can be used to predict the state of cancer in breast cancer patient.
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    Rajan, R., Karbowniczek, M., Pugsley, H. R., Sabnani, M. K., Astrinidis, A., and La-Beck, N. M. (2015) Quantifying autophagosomes and autolysosomes in cells using imaging flow cytometry Cytometry, Part A 87, 451– 458 DOI: 10.1002/cyto.a.22652
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    62
    Quantifying autophagosomes and autolysosomes in cells using imaging flow cytometry
    Rajan, Robin; Karbowniczek, Magdalena; Pugsley, Haley R.; Sabnani, Manoj K.; Astrinidis, Aristotelis; La-Beck, Ninh M.
    Cytometry, Part A (2015), 87 (5), 451-458CODEN: CPAYAV; ISSN:1552-4922. (Wiley-Blackwell)
    Autophagy dysregulation has been implicated in numerous diseases and many therapeutic agents are known to modulate this pathway. Therefore, the ability to accurately monitor autophagy is crit. to understanding its role in the pathogenesis and treatment of many diseases. Recently an imaging flow cytometry method measuring colocalization of microtubule assocd. protein 1B light chain 3 (LC3) and lysosomal signals via Bright Detail Similarity (BDS) was proposed which enabled evaluation of autophagic processing. However, since BDS only evaluates colocalization of LC3 and lysosomal signals, the no. of autophagy organelles was not taken into account. We found that in cells classified as having Low BDS, there was a large degree of variability in accumulation of autophagosomes. Therefore, we developed a new approach wherein BDS was combined with no. of LC3+ puncta, which enabled us to distinguish between cells having very few autophagy organelles vs. cells with accumulation of autophagosomes or autolysosomes. Using this method, we were able to distinguish and quantify autophagosomes and autolysosomes in breast cancer cells cultured under basal conditions, with inhibition of autophagy using chloroquine, and with induction of autophagy using amino acid starvation. This technique yields addnl. insight into autophagy processing making it a useful supplement to current techniques. © 2015 International Society for Advancement of Cytometry.
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    Hendershot, L. M. (2004) The ER function BiP is a master regulator of ER function Mt. Sinai J. Med. 71, 289– 297
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    63
    The ER function BiP is a master regulator of ER function
    Hendershot Linda M
    The Mount Sinai journal of medicine, New York (2004), 71 (5), 289-97 ISSN:0027-2507.
    The endoplasmic reticulum (ER) is a command center of the cell that is second only to the nucleus in terms of the breadth of its influence on other organelles and activities. It is a major site of protein synthesis, contains the cellular calcium stores that are an essential component of many signaling pathways, and is the proximal site of a signal transduction cascade that responds to cellular stress conditions and serves to maintain homeostasis of the cell. All eucaryotic cells possess an ER, which can comprise nearly 50% of the membranes of a cell. Its functions can be divided into those that occur on the cytosolic side of the membrane (where protein translation and signal transduction cascades occur) and the luminal space (where most other ER functions take place). Our studies during the past several years have revealed that the ER molecular chaperone BiP is a master regulator of ER function. It is responsible for maintaining the permeability barrier of the ER during protein translocation, directing protein folding and assembly, targeting misfolded proteins for retrograde translocation so they can be degraded by the proteasome, contributing to ER calcium stores, and sensing conditions of stress in this organelle, to activate the mammalian unfolded protein response.
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    Hou, S., Isaji, T., Hang, Q., Im, S., Fukuda, T., and Gu, J. (2016) Distinct effects of β1 integrin on cell proliferation and cellular signaling in MDA-MB-231 breast cancer cells Sci. Rep. 6, 18430 DOI: 10.1038/srep18430
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    64
    Distinct effects of β1 integrin on cell proliferation and cellular signaling in MDA-MB-231 breast cancer cells
    Hou, Sicong; Isaji, Tomoya; Hang, Qinglei; Im, Sanghun; Fukuda, Tomohiko; Gu, Jianguo
    Scientific Reports (2016), 6 (), 18430CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
    An aberrant expression of integrin β1 has been implicated in breast cancer progression. Here, we compared the cell behaviors of wild-type (WT), β1 gene deleted (KO), and β1 gene restored (Res) MDA-MB-231 cells. Surprisingly, the expression of β1 exhibited opposite effects on cell proliferation. These effects were dependent on cell densities, and they showed an up-regulation of cell proliferation when cells were cultured under sparse conditions, and a down-regulation of cell growth under dense conditions. By comparison with WT cells, the phosphorylation levels of ERK in KO cells were consistently suppressed under sparse culture conditions, but consistently up-regulated under dense culture conditions. The phosphorylation levels of EGFR were increased in the KO cells. By contrast, the phosphorylation levels of AKT were decreased in the KO cells. The abilities for both colony and tumor formation were significantly suppressed in the KO cells, suggesting that β1 plays an important role in cell survival signaling for tumorigenesis. These aberrant phenotypes in the KO cells were rescued in the Res cells. Taken together, these results clearly showed the distinct roles of β1 in cancer cells: the inhibition of cell growth and the promotion of cell survival, which may shed light on cancer therapies.
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    Hu, Y., Sun, Z., Deng, J., Hu, B., Yan, W., Wei, H., and Jiang, J. (2017) Splicing factor hnRNPA2B1 contributes to tumorigenic potential of breast cancer cells through STAT3 and ERK1/2 signaling pathway Tumor Biol. 39, 101042831769431 DOI: 10.1177/1010428317694318
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    Belizzi, A., Greco, M. R., Rubino, R., Paradiso, A., Forciniti, S., Zeeberg, K., Cardone, R. A., and Reshkin, S. J. (2015) The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells Int. J. Oncol. 46, 1214– 1224 DOI: 10.3892/ijo.2014.2805
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    Genovese, G., Ghosh, P., Li, H., Rettino, A., Sioletic, S., Cittadini, A., and Sgambato, A. (2012) The tumor suppressor HINT1 regulates MITF and β-catenin transcriptional activity in melanoma cells Cell Cycle 11, 2206– 2215 DOI: 10.4161/cc.20765
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    The tumor suppressor HINT1 regulates MITF and β-catenin transcriptional activity in melanoma cells
    Genovese, Giannicola; Ghosh, Papia; Li, Haiyang; Rettino, Alessando; Sioletic, Stefano; Cittadini, Achille; Sgambato, Alessandro
    Cell Cycle (2012), 11 (11), 2206-2215CODEN: CCEYAS; ISSN:1538-4101. (Landes Bioscience)
    Histidine triad nucleotide-binding protein 1 (HINT1) is a haploinsufficient tumor suppressor gene that inhibits the Wnt/β-catenin pathway in colon cancer cells and Microphthalmia-assocd. transcription factor (MITF) activity in human mast cells. MITF and β-catenin play a central role in melanocyte and melanoma cell survival, and this study aimed to investigate the effects of HINT1 on the MITF and β-catenin pathways in malignant melanoma cells. We found that HINT1 inhibits MITF and β-catenin transcriptional activity, and both proteins can be co-immunopptd. with an anti-HINT1-specific antibody in melanoma cell lines. Stable, constitutive overexpression of the HINT1 protein in human melanoma cells significantly impaired cell proliferation in vitro and tumorigenesis in vivo. These effects were assocd. with a decreased expression of cyclin D1 and BCL2, well known MITF and β-catenin transcription targets, resp. We also demonstrated that BCL2 and cyclin D1 can partially rescue the HINT1-driven phenotype. Moreover, we found in ChIP assays that HINT1 binds the chromatin at MITF and β-catenin sites in BCL2 and cyclin D1 promoters, resp., and that mSIN3a and HDAC1, well known transcriptional repressors, can be co-immunopptd. with an anti-HINT1-specific antibody. These findings support the tumor suppressor activity of HINT1 gene in melanoma cells by promoting the formation of non-functional complexes with oncogenic transcription factors like MITF and β-catenin.
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  68. 68
    Verdel, A. and Khochbin, S. (1999) Identification of a new family of higher eukaryotic histone deacetylases. Coordinate expression of differentiation-dependent chromatin modifiers J. Biol. Chem. 274, 2440– 2445 DOI: 10.1074/jbc.274.4.2440
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    Identification of a new family of higher eukaryotic histone deacetylases Coordinate expression of differentiation-dependent chromatin modifiers
    Verdel, Andre; Khochbin, Saadi
    Journal of Biological Chemistry (1999), 274 (4), 2440-2445CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    The histone deacetylase domain of almost all members of higher eukaryotic histone deacetylases already identified (HDAC family) is highly homologous to that of yeast RPD3. In this paper we report the cloning of two cDNAs encoding members of a new family of histone deacetylase in mouse that show a better homol. to yeast HDA1 histone deacetylase. These cDNAs encode relatively large proteins, presenting an in vitro trichostatin A-sensitive histone deacetylase activity. Interestingly, one, mHDA2, encodes a protein with two putative deacetylase domains, and the other, mHDA1, contains only one deacetylase homol. domain, located at the C-terminal half of the protein. Our data showed that these newly identified genes could belong to a network of genes coordinately regulated and involved in the remodeling of chromatin during cell differentiation. Indeed, the expression of mHDA1 and mHDA2 is tightly linked to the state of cell differentiation, behaving therefore like the histone H1° -encoding gene. Moreover, like histone H1° gene, mHDA1 and mHDA2 gene expression is induced upon deacetylase inhibitor treatment. We postulate the existence of a regulatory mechanism, commanding a coordinate expression of a group of genes involved in the remodeling of chromatin not only during cell differentiation but also after abnormal histone acetylation.
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  69. 69
    Tong, A., Zhang, H., Li, Z., Gou, L., Wang, Z., Wei, H., Tang, M., Liang, S., Chen, L., Huang, C., and Wei, Y. (2008) Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid Cancer Chemother. Pharmacol. 61, 791– 802 DOI: 10.1007/s00280-007-0536-2
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    69
    Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid
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    Cancer Chemotherapy and Pharmacology (2008), 61 (5), 791-802CODEN: CCPHDZ; ISSN:0344-5704. (Springer)
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  • Abstract

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    Figure 1

    Figure 1. Quantitative real-time PCR analysis of the transcript levels of RAD-50, NTRK2, BIG-3, PKCε, PKCι, and ERGIC-2 in MDA-MB231 cells exposed to either 8.45 μM (A) JAHA or (B) SAHA for 24 h (RAD-50 and NTRK2) or 48 h (BIG-3, PKCε, PKCι, and ERGIC-2). Beta-actin was used as an internal control. Values are the mean ± s.e.m. of two quadruplicate experiments. ∗ indicates p < 0.01 (student’s t test).

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    Figure 2

    Figure 2. Quantitative real-time PCR analysis of the transcript levels of gelsolin, IDI1, and VDPU1 in MDA-MB231 cells exposed to 8.45 μM JAHA for 48 h. Beta-actin was used as an internal control. Values are the mean ± s.e.m. of two quadruplicate experiments. ∗ indicates p < 0.01 (student’s t test).

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    Figure 3

    Figure 3. (A) Representative micrographs of cell comets obtained from MDA-MB231 TNBC cells stained with Vista Green DNA Dye, observed with a Nikon Microphot SA fluorescence microscope: (a) control cells, (b) cells treated with 2.5 μM VP16 for 48 h, (c) cells treated with 8.45 μM JAHA for 48 h, and (d) cells cotreated with 8.45 μM JAHA and 2.5 μM VP16 for 48 h. Microscopic magnification = 400×. (B) Histograms showing the olive tail moment of the scored cells exposed to VP16, JAHA, and VP16/JAHA, as compared to control (n = 60 for each experimental condition). Values are the mean ± s.e.m. of the results obtained. ∗ indicates p < 0.05 (student’s t test).

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      PURPOSE OF REVIEW: Triple-negative breast cancer (TNBC) is clinically characterized by the lack of expression of the estrogen receptor/progesterone receptor and the human epidermal growth factor receptor 2. It is highly heterogeneous and exhibits considerable overlap with basal-like and BRCA-related breast cancers. Constituting 15-20% of breast cancers, TNBC exhibits an aggressive phenotype with a poor prognosis. This review summarizes recent progress and studies in TNBC and discusses some of the ongoing clinical trials and emerging therapies for the treatment of TNBC. RECENT FINDINGS: Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay for treatment of this disease. The use of targeted agents such as bevacizumab, epidermal growth factor receptor and polyadenosine diphosphate-ribose polymerase inhibitors have led to conflicting results. However, recent research has prompted evaluation of additional drugs targeting multiple signaling pathways and epigenetic modifications for the treatment of this disease. SUMMARY: TNBC remains a challenging disease to treat with recent trials having demonstrated only modest improvements in outcomes. Increased understanding of the heterogeneity of this complex subtype may help tailor therapies to specific patient subgroups.
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      Suberoylanilide hydroxamic acid (SAHA) is a prototype of the newly developed, 2nd-generation, hybrid polar compds. It is a novel histone deacetylase inhibitor with high potency for inducing cell differentiation of cultured murine erythroleukemia cells. Human breast cancer cell lines MCF7, MDA-MB-231, and MDA-MB-435, as well as normal cells, including the normal breast epithelial cell line MCF-10A, and fibroblasts, were treated with SAHA. SAHA induced growth inhibition, cell cycle arrest, and eventual apoptosis in the breast cancer cells, possibly by modulating cell cycle- and apoptosis-regulatory proteins, such as cyclin-dependent kinase inhibitors p21 and p27, pRb, and other differentiation- and/or growth inhibition-assocd. genes, including gelsolin, isopentenyl diphosphate δ-isomerase and 1,25-dihydroxyvitamin D3 up-regulated protein 1. This, together with the low toxicity in normal cells, suggests that SAHA might have therapeutic potential for the treatment of human breast cancers.
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      Librizzi, Mariangela; Spencer, John; Luparello, Claudio
      International Journal of Molecular Sciences (2016), 17 (8), 1235/1-1235/11CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      We examd. the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-neg.) in the form of both a cocktail of the sep. compds. and a chem. synthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle anal. showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addn., the results suggest that the two distinct classes of compds. under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biol. activities of target cells and also showing the hybrid compd. as an addnl. promising drug-like mol. for the prevention or therapy of "aggressive" breast carcinoma.
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    7. 7
      Feng, X., Han, H., Zou, D., Zhou, J., and Zhou, W. (2017) Suberoylanilide hydroxamic acid-induced specific epigenetic regulation controls leptin-induced proliferation of breast cancer cell lines Oncotarget 8, 3364– 3379 DOI: 10.18632/oncotarget.13764
      There is no corresponding record for this reference.
    8. 8
      Kim, S. A., Jin, Y. L., and Kim, H. S. (2009) Structure-activity relationship studies of novel oxygen-incorporated SAHA analogues Arch. Pharmacal Res. 32, 15– 21 DOI: 10.1007/s12272-009-1113-5
      8
      Structure-activity relationship studies of novel oxygen-incorporated SAHA analogues
      Kim, Soon-Ai; Jin, Ying Lan; Kim, Hak Sung
      Archives of Pharmacal Research (2009), 32 (1), 15-21CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)
      Novel oxygen-incorporated SAHA (oxa-SAHA) analogs, in which oxygen was inserted in the alkyl linker connecting the hydroxamic acid moiety and amide group, were synthesized and their inhibitory activities on histone deacetylase were evaluated. The most active oxa-SAHA analog potently inhibited histone deacetylase, almost as potently as SAHA. Various structural modifications in the amide, but not the hydroxamic acid, significantly affected the inhibitory activities of the derivs. Based on the inhibitory data, the N-Ph moiety of the amide turned to be a better modification site for enhancing the inhibitory activity.
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    9. 9
      Spencer, J., Amin, J., Wang, M., Packham, G., Alwi, S. S., Tizzard, G. J., Coles, S. J., Paranal, R. M., Bradner, J. E., and Heightman, T. D. (2011) Synthesis and biological evaluation of JAHAs: ferrocene-based histone deacetylase inhibitors ACS Med. Chem. Lett. 2, 358– 362 DOI: 10.1021/ml100295v
      9
      Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors
      Spencer, John; Amin, Jahangir; Wang, Minghua; Packham, Graham; Alwi, Sharifah S. Syed; Tizzard, Graham J.; Coles, Simon J.; Paranal, Ronald M.; Bradner, James E.; Heightman, Tom D.
      ACS Medicinal Chemistry Letters (2011), 2 (5), 358-362CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      N1-Hydroxy-N8-ferrocenyloctanediamide, JAHA (7), an organometallic analog of SAHA contg. a ferrocenyl group as a Ph bioisostere, displays nanomolar inhibition of class I HDACs, excellent selectivity over class IIa HDACs, and anticancer action in intact cells (IC50 = 2.4 μM, MCF7 cell line). Mol. docking studies of 7 in HDAC8 (a,b) suggested that the ferrocenyl moiety in 7 can overlap with the aryl cap of SAHA and should display similar HDAC inhibition, which was borne out in an in vitro assay (IC50 values against HDAC8 (μM, SD in parentheses): SAHA, 1.41 (0.15)); 7, 1.36 (0.16). Thereafter, a small library of related JAHA analogs has been synthesized, and preliminary SAR studies are presented. IC50 values as low as 90 pM toward HDAC6 (class IIb) have been detd., highlighting the excellent potential of JAHAs as bioinorg. probes.
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    10. 10
      Marzenell, P., Hagen, H., Sellner, L., Zenz, T., Grinyte, R., Pavlov, V., Daum, S., and Mokhir, A. (2013) Aminoferrocene-based prodrugs and their effects on human normal and cancer cells as well as bacterial cells J. Med. Chem. 56, 6935– 6944 DOI: 10.1021/jm400754c
      10
      Aminoferrocene-Based Prodrugs and Their Effects on Human Normal and Cancer Cells as Well as Bacterial Cells
      Marzenell, Paul; Hagen, Helen; Sellner, Leopold; Zenz, Thorsten; Grinyte, Ruta; Pavlov, Valeri; Daum, Steffen; Mokhir, Andriy
      Journal of Medicinal Chemistry (2013), 56 (17), 6935-6944CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Aminoferrocene-based prodrugs are activated under cancer-specific conditions (high concn. of reactive oxygen species, ROS) with the formation of glutathione scavengers (p-quinone methide) and ROS-generating iron complexes. Herein, the authors explored three structural modifications of these prodrugs to improve their properties: (a) the attachment of a -COOH function to the ferrocene fragment leads to the improvement of water soly. and reactivity in vitro but also decreases cell-membrane permeability and biol. activity, (b) the alkylation of the N-benzyl residue does not show any significant affect, and (c) the attachment of the second arylboronic acid fragment improves the toxicity (IC50) of the prodrugs toward human promyelocytic leukemia cells (HL-60) from 52 to 12 μM. Finally, the authors demonstrated that the prodrugs are active against primary chronic lymphocytic leukemia (CLL) cells, with the best compds. exhibiting an IC50 value of 1.5 μM. The most active compds. were found to not affect mononuclear cells and representative bacterial cells.
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    11. 11
      Jaouen, G., Vessières, A., and Top, S. (2015) Ferrocifen type anti cancer drugs Chem. Soc. Rev. 44, 8802– 8817 DOI: 10.1039/C5CS00486A
      11
      Ferrocifen type anti cancer drugs
      Jaouen, Gerard; Vessieres, Anne; Top, Siden
      Chemical Society Reviews (2015), 44 (24), 8802-8817CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      Despite current developments in therapeutics focusing on biotechnol.-oriented species, the unflagging utility of small mols. or peptides in medicine is still producing strong results. In 2014 for example, of the 41 new medicines authorized for sale, 33 belonged to the category of small mols., while in 2013 they represented 24 of 27, according to the FDA. This can be explained as the result of recent forays into new or long-neglected areas of chem. Medicinal organometallic chem. can provide us with an antimalarial against resistant parasitic strains, as attested by the phase II clin. development of ferroquine, with a new framework for conceptual advances based on three-dimensional space-filling, and with redox or indeed catalytic intracellular properties. In this context, bioferrocene species with antiproliferative potential have for several years been the subject of sustained effort, based on some initial successes and on the nature of ferrocene as a stable arom., with low toxicity, low cost, and possessing reversible redox properties. We show here the different antitumoral approaches offered by ferrocifen derivs., originally simple derivs. of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity. These entities act via various targets, some of which have been identified, that are triggered according to the concn. of the products. They also act according to the nature of the cancer cells and their functionality, by mechanistic pathways that can operate either synergistically or not, in successive, concomitant or sequential ways, depending for example on newly identified signaling pathways inducing senescence or apoptosis. Here we present a first attempt to rationalize the behavior of these entities with various anticancer targets.
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    12. 12
      Leonidova, A., Anstaett, P., Pierroz, V., Mari, C., Spingler, B., Ferrari, S., and Gasser, G. (2015) Induction of cytotoxicity through photorelease of aminoferrocene Inorg. Chem. 54, 9740– 9748 DOI: 10.1021/acs.inorgchem.5b01332
      12
      Induction of Cytotoxicity through Photorelease of Aminoferrocene
      Leonidova, Anna; Anstaett, Philipp; Pierroz, Vanessa; Mari, Cristina; Spingler, Bernhard; Ferrari, Stefano; Gasser, Gilles
      Inorganic Chemistry (2015), 54 (20), 9740-9748CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      Reactive oxygen species (ROS)-activated aminoferrocene-based anticancer prodrug candidates successfully take advantage of intrinsically high amts. of ROS in tumor tissues. Interestingly, the ROS-initiated activation of these prodrug candidates leads to formation of unstable aminoferrocene (Fc-NH2) derivs., which decay to iron ions. The latter catalytically increases ROS concn. to a lethal level. In this work, we prepd. light-controlled aminoferrocene prodrug candidates by derivatizing Fc-NH2 with an o-nitrophenyl and an o-nitrobiphenyl photolabile protecting group (PLPG), resp., and by further conjugation to a mitochondria localization signal (MLS) peptide (Cys-D-Arg-Phe-Lys-NH2). The resulting bioconjugates were found to be more stable and less cytotoxic, in the dark, toward human promyelocytic leukemia cells (HL-60) compared to Fc-NH2. Upon light irradn. at 355 nm, both conjugates released Fc-NH2, albeit with very different photolysis quantum yields. The o-nitrobiphenyl photocage was in fact several orders of magnitude more efficient than the o-nitrophenyl photocage in releasing Fc-NH2. This difference was reflected by the light irradn. expts. on the HL-60 cell line, in which aminoferrocene conjugated with the o-nitrobiphenyl cage and the MLS displayed the highest phototoxicity index (2.5 ± 0.4) of all the compds. tested. The iron release assays confirmed the rise in iron ion concns. upon light irradn. of both caged aminoferrocene derivs. Together with the absence of phototoxicity on the nonmalignant hTERT-immortalized retinal pigment epithelial (hTERT RPE-1) cell line, these results indicate catalytic generation of ROS as possible mode of action.
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    13. 13
      Patra, M. and Gasser, G. (2017) The medicinal chemistry of ferrocene and its derivatives Nat. Rev. Chem. 1, 0066 DOI: 10.1038/s41570-017-0066
      13
      The medicinal chemistry of ferrocene and its derivatives
      Patra, Malay; Gasser, Gilles
      Nature Reviews Chemistry (2017), 1 (9), 0066CODEN: NRCAF7; ISSN:2397-3358. (Nature Research)
      A review. Ferrocene derivs. have attracted significant interest as anticancer, antibacterial, antifungal and antiparasitic drug candidates. Discovered in the 1990s, the two most prominent derivs., ferroquine and ferrocifen, have since been studied extensively for the treatment of malaria and cancer, resp. The ferrocenyl moiety in these two compds. participates in important metal-specific modes of action that contribute to the overall therapeutic efficacy of the mols. Although ferroquine is currently in phase II clin. trials and ferrocifen is in preclin. evaluation, no other ferrocene deriv. - in fact, no other non-radioactive organometallic compd. of any kind - has advanced into clin. trials. This Perspective delineates strategies for the systematic incorporation of ferrocenyl groups into known drugs or drug candidates, with a view to finding new drug leads. In addn., we provide a crit. evaluation of the difficulties assocd. with obtaining the clin. approval that would enable ferrocene-contg. mols. to transition from being synthetic curiosities to effective drugs.
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    14. 14
      Ocasio, C. A., Sansook, S., Jones, R., Roberts, J. M., Scott, T. G., Tsoureas, N., Coxhead, P., Guille, M., Tizzard, G. J., Coles, S. J., Hochegger, H., Bradner, J. E., and Spencer, J. (2017) Organometallics 36, 3276– 3283 DOI: 10.1021/acs.organomet.7b00437
      There is no corresponding record for this reference.
    15. 15
      Li, J., Liu, R., Lei, Y., Wang, K., Lau, Q. C., Xie, N., Zhou, S., Nie, C., Chen, L., Wei, Y., and Huang, C. (2010) Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells Autophagy 6, 711– 724 DOI: 10.4161/auto.6.6.12397
      There is no corresponding record for this reference.
    16. 16
      Librizzi, M., Chiarelli, R., Bosco, L., Sansook, S., Gascon, J. M., Spencer, J., Caradonna, F., and Luparello, C. (2015) The histone deacetylase inhibitor JAHA down-regulates pERK and global DNA methylation in MDA-MB231 breast cancer cells Materials 8, 7041– 7047 DOI: 10.3390/ma8105358
      There is no corresponding record for this reference.
    17. 17
      Sirchia, R. and Luparello, C. (2009) Short-term exposure to cadmium affects the expression of stress response and apoptosis-related genes in immortalized epithelial cells from the human breast Toxicol. In Vitro 23, 943– 949 DOI: 10.1016/j.tiv.2009.04.016
      There is no corresponding record for this reference.
    18. 18
      Luparello, C., Longo, A., and Vetrano, M. (2012) Exposure to cadmium chloride influences astrocyte-elevated gene-1 (AEG-1) expression in MDA-MB231 human breast cancer cells Biochimie 94, 207– 213 DOI: 10.1016/j.biochi.2011.10.009
      There is no corresponding record for this reference.
    19. 19
      Luparello, C., Sirchia, R., and Longo, A. (2013) Type V collagen and protein kinase C η down-regulation in 8701-BC breast cancer cells Mol. Carcinog. 52, 348– 358 DOI: 10.1002/mc.21856
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      Type V collagen and protein kinase C η down-regulation in 8701-BC breast cancer cells
      Luparello, Claudio; Sirchia, Rosalia; Longo, Alessandra
      Molecular Carcinogenesis (2013), 52 (5), 348-358CODEN: MOCAE8; ISSN:0899-1987. (Wiley-Blackwell)
      We previously reported that ductal infiltrating carcinomas (d.i.c.) of the human breast display profound modifications of the stromal architecture, assocd. with anomalous collagen compn. Among the major alterations obsd. in the interstitial collagen, the relative increase of type V collagen content was detected. When type V collagen was used as an "in vitro" substrate for 8701-BC d.i.c. cells, it appeared able to restrain cell growth, inhibit cell motility and invasion "in vitro", and modify the expression levels of genes coding for apoptosis factors, caspases and stress response proteins. In the present paper we demonstrate that type V collagen induces the down-regulation of protein kinase C η, an event that may be, at least in part, responsible of the previously-reported modifications of cell morphol. and growth rate, and that appears to be involved in the already-obsd. changes of expression levels of genes encoding for anti- (Bcl-2) and pro-apoptotic factors (Bad, Dapk, Bcl-Xs) and enzymes (caspase 5 and 8). © 2011 Wiley Periodicals, Inc.
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    20. 20
      Sokolov, B. P. and Prockop, D. J. (1994) A rapid and simple PCR-based method for isolation of cDNAs from differentially expressed genes Nucleic Acids Res. 22, 4009– 4015 DOI: 10.1093/nar/22.19.4009
      There is no corresponding record for this reference.
    21. 21
      Naselli, F., Belshaw, N. J., Gentile, C., Tutone, M., Tesoriere, L., Livrea, M. A., and Caradonna, F. (2015) Phytochemical indicaxanthin inhibits colon cancer cell growth and affects the DNA methylation status by influencing epigenetically modifying enzyme expression and activity J. Nutrigenet. Nutrigenomics 8, 114– 127 DOI: 10.1159/000439382
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      Phytochemical Indicaxanthin Inhibits Colon Cancer Cell Growth and Affects the DNA Methylation Status by Influencing Epigenetically Modifying Enzyme Expression and Activity
      Naselli, Flores; Belshaw, Nigel Junior; Gentile, Carla; Tutone, Marco; Tesoriere, Luisa; Livrea, Maria Antonietta; Caradonna, Fabio
      Journal of Nutrigenetics and Nutrigenomics (2015), 8 (3), 114-127CODEN: JNNOBS; ISSN:1661-6499. (S. Karger AG)
      Background: Recently, we have shown anti-proliferative and pro-apoptotic effects of indicaxanthin assocd. with epigenetic modulation of the onco-suppressor p16INK4a in the human colon cancer cell line CACO2. In the present study, the epigenetic activity of indicaxanthin and the mechanisms involved were further investigated in other colorectal cancer cell lines. Methods: LOVO1, CACO2, HT29, HCT116, and DLD1 cells were used to evaluate the potential influence of consistent dietary concns. of indicaxanthin on DNA methylation, and the epigenetic mechanisms involved were researched. Results: Indicaxanthin exhibited anti-proliferative activity in all cell lines but HT29, induced demethylation in the promoters of some methylation-silenced onco-suppressor genes involved in colorectal carcinogenesis (p16INK4a, GATA4, and ESR1), and left unchanged others which were basally hypermethylated (SFRP1 and HPP1). In apparent contrast, cell exposure to indicaxanthin increased DNMT gene expression, although indicaxanthin appeared to be an inhibitor of DNMT activity. Indicaxanthin also increased the expression of genes involved in DNA demethylation. Finally, an in silico mol. modeling approach suggested stable binding of indicaxanthin at the DNMT1 catalytic site. Conclusions: Our findings contribute to new knowledge in the field of phytochems. and specifically suggest dietary indicaxanthin as a potential epigenetic agent to protect colon cells against tumoral alterations.
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    22. 22
      Rozek, W., Kwasnik, M., Debski, J., and Zmudzinski, J. F. (2013) Mass spectrometry identification of granins and other proteins secreted by neuroblastoma cells Tumor Biol. 34, 1773– 1781 DOI: 10.1007/s13277-013-0716-0
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      Mass spectrometry identification of granins and other proteins secreted by neuroblastoma cells
      Rozek, Wojciech; Kwasnik, Malgorzata; Debski, Janusz; Zmudzinski, Jan F.
      Tumor Biology (2013), 34 (3), 1773-1781CODEN: TUMBEA; ISSN:1010-4283. (Springer)
      We used mass spectrometry-based protein identification to det. the presence of granins and other proteins in the mouse neuroblastoma secretome. We detected polypeptides derived from four members of the granin family: chromogranin A, chromogranin B, secretogranin III, and VGF. Many of them are derived from previously described biol. active regions; however, for VGF and CgB, we detected peptides not related to known bioactivities. Along with granins, we identified 115 other proteins secreted by mouse neuroblastoma cells, belonging to different functional categories. Fifty-six out of 119 detected proteins possess the signal fragments required for translocation into endoplasmic reticulum. Sequences of remaining 63 proteins were analyzed using SecretomeP algorithm to det. probability of nonclassical secretion. Identified proteins are involved in the regulation of cell cycle, proliferation, apoptosis, angiogenesis, proteolysis, and cell adhesion.
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    23. 23
      Bakun, M., Senatorski, G., Rubel, T., Lukasik, A., Zielenkiewicz, P., Dadlez, M., and Paczek, L. (2014) Urine proteomes of healthy aging humans reveal extracellular matrix (ECM) alterations and immune system dysfunction Age (Dordr.) 36, 299– 311 DOI: 10.1007/s11357-013-9562-7
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      Urine proteomes of healthy aging humans reveal extracellular matrix (ECM) alterations and immune system dysfunction
      Bakun M; Senatorski G; Rubel T; Lukasik A; Zielenkiewicz P; Dadlez M; Paczek L
      Age (Dordrecht, Netherlands) (2014), 36 (1), 299-311 ISSN:.
      Aging is a complex physiological process that poses considerable conundrums to rapidly aging societies. For example, the risk of dying from cardiovascular diseases and/or cancer steadily declines for people after their 60s, and other causes of death predominate for seniors older than 80 years of age. Thus, physiological aging presents numerous unanswered questions, particularly with regard to changing metabolic patterns. Urine proteomics analysis is becoming a non-invasive and reproducible diagnostic method. We investigated the urine proteomes in healthy elderly people to determine which metabolic processes were weakened or strengthened in aging humans. Urine samples from 37 healthy volunteers aged 19-90 years (19 men, 18 women) were analyzed for protein expression by liquid chromatography-tandem mass spectrometry. This generated a list of 19 proteins that were differentially expressed in different age groups (young, intermediate, and old age). In particular, the oldest group showed protein changes reflective of altered extracellular matrix turnover and declining immune function, in which changes corresponded to reported changes in cardiovascular tissue remodeling and immune disorders in the elderly. Thus, urinary proteome changes in the elderly appear to reflect the physiological processes of aging and are particularly clearly represented in the circulatory and immune systems. Detailed identification of "protein trails" creates a more global picture of metabolic changes that occur in the elderly.
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    24. 24
      Gluz, O., Liedtke, C., Gottschalk, N., Pusztai, L., Nitz, U., and Harbeck, N. (2009) Triple-negative breast cancer - current status and future directions Ann. Oncol. 20, 1913– 1927 DOI: 10.1093/annonc/mdp492
      24
      Triple-negative breast cancer--current status and future directions
      Gluz O; Liedtke C; Gottschalk N; Pusztai L; Nitz U; Harbeck N
      Annals of oncology : official journal of the European Society for Medical Oncology (2009), 20 (12), 1913-27 ISSN:.
      Triple-negative breast cancer (TNBC) is defined by a lack of expression of both estrogen and progesterone receptor as well as human epidermal growth factor receptor 2. It is characterized by distinct molecular, histological and clinical features including a particularly unfavorable prognosis despite increased sensitivity to standard cytotoxic chemotherapy regimens. TNBC is highly though not completely concordant with various definitions of basal-like breast cancer (BLBC) defined by high-throughput gene expression analyses. The lack in complete concordance may in part be explained by both BLBC and TNBC comprising entities that in themselves are heterogeneous. Numerous efforts are currently being undertaken to improve prognosis for patients with TNBC. They comprise both optimization of choice and scheduling of common cytotoxic agents (i.e. addition of platinum salts or dose intensification strategies) and introduction of novel agents (i.e. poly-ADP-ribose-polymerase-1 inhibitors, agents targeting the epidermal growth factor receptor, multityrosine kinase inhibitors or antiangiogenic agents).
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    25. 25
      Librizzi, M., Longo, A., Chiarelli, R., Amin, J., Spencer, J., and Luparello, C. (2012) Cytotoxic effects of Jay Amin hydroxamic acid (JAHA), a ferrocene-based class I histone deacetylase inhibitor, on triple-negative MDA-MB231 breast cancer cells Chem. Res. Toxicol. 25, 2608– 2616 DOI: 10.1021/tx300376h
      There is no corresponding record for this reference.
    26. 26
      Howe, E. N., Cochrane, D. R., and Richer, J. K. (2011) Targets of miR-200c mediate suppression of cell motility and anoikis resistance Breast Cancer Res. 13, R45 DOI: 10.1186/bcr2867
      26
      Targets of miR-200c mediate suppression of cell motility and anoikis resistance
      Howe, Erin N.; Cochrane, Dawn R.; Richer, Jennifer K.
      Breast Cancer Research (2011), 13 (), R45CODEN: BRCRFS; ISSN:1465-542X. (BioMed Central Ltd.)
      Introduction: miR-200c and other members of the miR-200 family promote epithelial identity by directly targeting ZEB1 and ZEB2, which repress E-cadherin and other genes involved in polarity. Loss of miR-200c is often obsd. in carcinoma cells that have undergone epithelial to mesenchymal transition (EMT). Restoration of miR-200c to such cells leads to a redn. in stem cell-like characteristics, reduced migration and invasion, and increased sensitivity to taxanes. Here we investigate the functional role of novel targets of miR-200c in the aggressive behavior of breast and endometrial cancer cells. Methods: Putative target genes of miR-200c identified by microarray profiling were validated as direct targets using dual luciferase reporter assays. Following restoration of miR-200c to triple neg. breast cancer and type 2 endometrial cancer cell lines that had undergone EMT, levels of endogenous target mRNA and resp. protein products were measured. Migration and sensitivity to anoikis were detd. using wound healing assays or cell-death ELISAs and viability assays resp. Results: We found that restoration of miR-200c suppresses anoikis resistance, a novel function for this influential miRNA. We identified novel targets of miR-200c, including genes encoding fibronectin 1 (FN1), moesin (MSN), neurotrophic tyrosine receptor kinase type 2 (NTRK2 or TrkB), leptin receptor (LEPR), and Rho GTPase activating protein 19 (ARHGAP19). These targets all encode proteins normally expressed in cells of mesenchymal or neuronal origin; however, in carcinoma cells that lack miR-200c they become aberrantly expressed and contribute to the EMT phenotype and aggressive behavior. We showed that these targets are inhibited upon restoration of miR-200c to aggressive breast and endometrial cancer cells. We demonstrated that inhibition of MSN and/or FN1 is sufficient to mediate the ability of miR-200c to suppress cell migration. Lastly, we showed that targeting of TrkB mediates the ability of miR-200c to restore anoikis sensitivity. Conclusions: Thus, miR-200c maintains the epithelial phenotype not only by targeting ZEB1/2, which usually facilitates restoration of E-cadherin expression, but also by actively repressing a program of mesenchymal and neuronal genes involved in cell motility and anoikis resistance.
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    27. 27
      Kim, M. S., Lee, W. S., Jeong, J., Kim, S. J., and Jin, W. (2015) Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer Oncotarget 6, 40158– 40171 DOI: 10.18632/oncotarget.5522
      There is no corresponding record for this reference.
    28. 28
      Fujita, K., Tatsumi, K., Kondoh, E., Chigusa, Y., Mogami, H., Fujii, T., Yura, S., Kakui, K., and Konishi, I. (2011) Differential expression and the anti-apoptotic effect of human placental neurotrophins and their receptors Placenta 32, 737– 744 DOI: 10.1016/j.placenta.2011.07.001
      There is no corresponding record for this reference.
    29. 29
      Yang, J. L., Lin, Y. T., Chuang, P. C., Bohr, V. A., and Mattson, M. P. (2014) BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1 NeuroMol. Med. 16, 161– 174 DOI: 10.1007/s12017-013-8270-x
      29
      BDNF and Exercise Enhance Neuronal DNA Repair by Stimulating CREB-Mediated Production of Apurinic/Apyrimidinic Endonuclease 1
      Yang, Jenq-Lin; Lin, Yu-Ting; Chuang, Pei-Chin; Bohr, Vilhelm A.; Mattson, Mark P.
      NeuroMolecular Medicine (2014), 16 (1), 161-174CODEN: NMEEAN; ISSN:1535-1084. (Humana Press Inc.)
      Brain-derived neurotrophic factor (BDNF) promotes the survival and growth of neurons during brain development and mediates activity-dependent synaptic plasticity and assocd. learning and memory in the adult. BDNF levels are reduced in brain regions affected in Alzheimer's, Parkinson's, and Huntington's diseases, and elevation of BDNF levels can ameliorate neuronal dysfunction and degeneration in exptl. models of these diseases. Because neurons accumulate oxidative lesions in their DNA during normal activity and in neurodegenerative disorders, we detd. whether and how BDNF affects the ability of neurons to cope with oxidative DNA damage. We found that BDNF protects cerebral cortical neurons against oxidative DNA damage-induced death by a mechanism involving enhanced DNA repair. BDNF stimulates DNA repair by activating cAMP response element-binding protein (CREB), which, in turn, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair pathway. Suppression of either APE1 or TrkB by RNA interference abolishes the ability of BDNF to protect neurons against oxidized DNA damage-induced death. The ability of BDNF to activate CREB and upregulate APE1 expression is abolished by shRNA of TrkB as well as inhibitors of TrkB, PI3 kinase, and Akt kinase. Voluntary running wheel exercise significantly increases levels of BDNF, activates CREB, and upregulates APE1 in the cerebral cortex and hippocampus of mice, suggesting a novel mechanism whereby exercise may protect neurons from oxidative DNA damage. Our findings reveal a previously unknown ability of BDNF to enhance DNA repair by inducing the expression of the DNA repair enzyme APE1.
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    30. 30
      Zhang, D., Tang, B., Xie, X., Xiao, Y. F., Yang, S. M., and Zhang, J. W. (2015) The interplay between DNA repair and autophagy in cancer therapy Cancer Biol. Ther. 16, 1005– 1013 DOI: 10.1080/15384047.2015.1046022
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      The interplay between DNA repair and autophagy in cancer therapy
      Zhang, Dan; Tang, Bo; Xie, Xia; Xiao, Yu-Feng; Yang, Shi-Ming; Zhang, Jian-Wei
      Cancer Biology & Therapy (2015), 16 (7), 1005-1013CODEN: CBTAAO; ISSN:1555-8576. (Taylor & Francis Ltd.)
      DNA is the prime target of anticancer treatments. DNA damage triggers a series of signaling cascades promoting cellular survival, including DNA repair, cell cycle arrest, and autophagy. The elevated basal and/or stressful levels of both DNA repair and autophagy obsd. in tumor cells, in contrast to normal cells, have been identified as the most important drug-responsive programs that impact the outcome of anticancer therapy. The exact relationship between DNA repair and autophagy in cancer cells remains unclear. On one hand, autophagy has been shown to regulate some of the DNA repair proteins after DNA damage by maintaining the balance between their synthesis, stabilization, and degrdn. One the other hand, some evidence has demonstrated that some DNA repair mol. have a crucial role in the initiation of autophagy. In this review, we mainly discuss the interplay between DNA repair and autophagy in anticancer therapy and expect to enlighten some effective strategies for cancer treatment.
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    31. 31
      Lee, J. H., Choy, M. L., Ngo, L., Foster, S. S., and Marks, P. A. (2010) Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair Proc. Natl. Acad. Sci. U. S. A. 107, 14639– 14644 DOI: 10.1073/pnas.1008522107
      31
      Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair
      Lee, J.-H.; Choy, M. L.; Ngo, L.; Foster, S. S.; Marks, Paul A.
      Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (33), 14639-14644, S14639/1-S14639/2CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, we show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (γH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-h culture of cells with vorinostat, and reculture without the HDACi, γH2AX was undetectable by 2 h in normal cells, while persisting in transformed cells for the duration of culture. Further, we found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is assocd. with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concns. that cause little or no normal cell death.
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    32. 32
      Jeong, W., Bae, S. H., Toledano, M. B., and Rhee, S. G. (2012) Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression Free Radical Biol. Med. 53, 447– 456 DOI: 10.1016/j.freeradbiomed.2012.05.020
      32
      Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression
      Jeong, Woojin; Bae, Soo Han; Toledano, Michel B.; Rhee, Sue Goo
      Free Radical Biology & Medicine (2012), 53 (3), 447-456CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
      A review. Peroxiredoxins (Prxs) constitute a family of peroxidases in which Cys serves as the primary site of oxidn. during the redn. of peroxides. Members of the 2-Cys Prx subfamily of Prxs (Prx I to IV in mammals) are inactivated via hyperoxidn. of the active site Cys residue to sulfinic acid (Cys-SO2H) during catalysis and are reactivated via an ATP-consuming reaction catalyzed by sulfiredoxin (Srx). This reversible hyperoxidn. reaction has been proposed to protect H2O2 signaling mols. from premature removal by 2-Cys Prxs or to up-regulate the chaperone function of these enzymes. In addn. to its sulfinic acid reductase activity, Srx catalyzes the removal of glutathione (deglutathionylation) from modified proteins. The physiol. relevance of both the reversible hyperoxidn. of 2-Cys Prxs and the deglutathionylation catalyzed by Srx remains unclear. Recent findings have revealed that Srx expression is induced in mammalian cells under a variety of conditions, such as in metabolically stimulated pancreatic β-cells, in immunostimulated macrophages, in neuronal cells engaged in synaptic communication, in lung cells exposed to hyperoxia or cigarette smoke, in hepatocytes of EtOH-fed animals, and in several types of cells exposed to chemopreventive agents. Such induction of Srx in mammalian cells is regulated at the transcriptional level, predominantly via activator protein-1 and/or nuclear factor erythroid 2-related factor 2. Srx expression is also regulated at the translational level in Saccharomyces cerevisiae.
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    33. 33
      Avval, F. Z. and Holmgren, A. (2009) Molecular mechanisms of thioredoxin and glutaredoxin as hydrogen donors for Mammalian s phase ribonucleotide reductase J. Biol. Chem. 284, 8233– 8240 DOI: 10.1074/jbc.M809338200
      There is no corresponding record for this reference.
    34. 34
      Butinar, M., Prebanda, M. T., Rajković, J., Jerič, B., Stoka, V., Peters, C., Reinheckel, T., Krüger, A., Turk, V., Turk, B., and Vasiljeva, O. (2014) Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model Oncogene 33, 3392– 3400 DOI: 10.1038/onc.2013.314
      There is no corresponding record for this reference.
    35. 35
      Bose, P., Dai, Y., and Grant, S. (2014) Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights Pharmacol. Ther. 143, 323– 336 DOI: 10.1016/j.pharmthera.2014.04.004
      35
      Histone deacetylase inhibitor (HDACI) mechanisms of action: Emerging insights
      Bose, Prithviraj; Dai, Yun; Grant, Steven
      Pharmacology & Therapeutics (2014), 143 (3), 323-336CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)
      A review. Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addn. to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clin. studies. In recent years, addnl. mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, crit. to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clin. potential, the clin. use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.
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    36. 36
      Gatei, M., Kijas, A. W., Biard, D., Dörk, T., and Lavin, M. F. (2014) RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress Hum. Mol. Genet. 23, 4232– 4248 DOI: 10.1093/hmg/ddu141
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      RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress
      Gatei, Magtouf; Kijas, Amanda W.; Biard, Denis; Doerk, Thilo; Lavin, Martin F.
      Human Molecular Genetics (2014), 23 (16), 4232-4248CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
      The MRE11/RAD50/NBN (MRN) complex plays a key role in detecting DNA double-strand breaks, recruiting and activating ataxia-telangiectasia mutated and in processing the breaks. Members of this complex also act as adaptor mols. for downstream signaling to the cell cycle and other cellular processes. Somewhat more controversial are the results to support a role for MRN in the ataxia-telangiectasia and Rad3-related (ATR) activation and signaling. We provide evidence that RAD50 is required for ATR activation in mammalian cells in response to DNA replication stress. It is in turn phosphorylated at a specific site (S635) by ATR, which is required for ATR signaling through Chk1 and other downstream substrates. We find that RAD50 phosphorylation is essential for DNA replication restart by promoting loading of cohesin at these sites. We also demonstrate that replication stress-induced RAD50 phosphorylation is functionally significant for cell survival and cell cycle checkpoint activation. These results highlight the importance of the adaptor role for a member of the MRN complex in all aspects of the response to DNA replication stress.
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    37. 37
      Brezniceanu, M. L., Völp, K., Bösser, S., Solbach, C., Lichter, P., Joos, S., and Zörnig, M. (2003) HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma FASEB J. 17, 1295– 1297 DOI: 10.1096/fj.02-0621fje
      There is no corresponding record for this reference.
    38. 38
      Chang, B. P., Wang, D. S., Xing, J. W., Yang, S. H., Chu, Q., and Yu, S. Y. (2014) miR-200c inhibits metastasis of breast cancer cells by targeting HMGB1 J. Huazhong Univ. Sci. Technol., Med. Sci. 34, 201– 206 DOI: 10.1007/s11596-014-1259-3
      There is no corresponding record for this reference.
    39. 39
      Krynetskaia, N. F., Phadke, M. S., Jadhav, S. H., and Krynetskiy, E. Y. (2009) Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage Mol. Cancer Ther. 8, 864– 872 DOI: 10.1158/1535-7163.MCT-08-0695
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      Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage
      Krynetskaia, Natalia F.; Phadke, Manali S.; Jadhav, Sachin H.; Krynetskiy, Evgeny Y.
      Molecular Cancer Therapeutics (2009), 8 (4), 864-872CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
      The identification of new mol. components of the DNA damage signaling cascade opens novel avenues to enhance the efficacy of chemotherapeutic drugs. High-mobility group protein 1 (HMGB1) is a DNA damage sensor responsive to the incorporation of nonnatural nucleosides into DNA; several nuclear and cytosolic proteins are functionally integrated with HMGB1 in the context of DNA damage response. The functional role of HMGB1 and HMGB1-assocd. proteins (high-mobility group protein B2, HMGB2; glyceraldehyde-3-phosphate dehydrogenase, GAPDH; protein disulfide isomerase family A member 3, PDIA3; and heat shock 70 kDa protein 8, HSPA8) in DNA damage response was assessed in human carcinoma cells A549 and UO31 by transient knockdown with short interfering RNAs. Using the cell proliferation assay, we found that knockdown of HMGB1-assocd. proteins resulted in 8-fold to 50-fold decreased chemosensitivity of A549 cells to cytarabine. Western blot anal. and immunofluorescent microscopy were used to evaluate genotoxic stress markers in knocked-down cancer cells after 24 to 72 h of incubation with 1 μmol/L of cytarabine. Our results dissect the roles of HMGB1-assocd. proteins in DNA damage response: HMGB1 and HMGB2 facilitate p53 phosphorylation after exposure to genotoxic stress, and PDIA3 has been found essential for H2AX phosphorylation (no γ-H2AX accumulated after 24-72 h of incubation with 1 μmol/L of cytarabine in PDIA3 knockdown cells). We conclude that phosphorylation of p53 and phosphorylation of H2AX occur in two distinct branches of the DNA damage response. These findings identify new mol. components of the DNA damage signaling cascade and provide novel promising targets for chemotherapeutic intervention.
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    40. 40
      Tsai, H. Y., Yang, Y. F., Wu, A. T., Yang, C. J., Liu, Y. P., Jan, Y. H., Lee, C. H., Hsiao, Y. W., Yeh, C. T., Shen, C. N., Lu, P. J., Huang, M. S., and Hsiao, M. (2013) Endoplasmic reticulum ribosome-binding protein 1 (RRBP1) overexpression is frequently found in lung cancer patients and alleviates intracellular stress-induced apoptosis through the enhancement of GRP78 Oncogene 32, 4921– 4931 DOI: 10.1038/onc.2012.514
      There is no corresponding record for this reference.
    41. 41
      Kelland, L. R., Smith, V., Valenti, M., Patterson, L., Clarke, P. A., Detre, S., End, D., Howes, A. J., Dowsett, M., Workman, P., and Johnston, S. R. (2001) Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer Clin. Cancer Res. 7, 3544– 3550
      41
      Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer
      Kelland, Lloyd R.; Smith, Vicki; Valenti, Melanie; Patterson, Lisa; Clarke, Paul A.; Detre, Simone; End, Dave; Howes, Angela J.; Dowsett, Mitch; Workman, Paul; Johnston, Stephen R. D.
      Clinical Cancer Research (2001), 7 (11), 3544-3550CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      Antitumor and pharmacodynamic studies were performed in MCF-7 human breast cancer cells and companion xenografts with the farnesyl protein transferase inhibitor, R115777, presently undergoing Phase II clin. trials, including in breast cancer. R115777 inhibited the growth of MCF-7 cells in vitro with an IC50 of 0.31 ± 0.25 μM. Exposure of MCF-7 cells to increasing concns. of R115777 for 24 h resulted in the inhibition of protein farnesylation, as indicated by the appearance of prelamin A at concns. >1 μM. After continuous exposure to 2 μM R115777, prelamin A levels peaked at 2 h post drug exposure and remained high for up to 72 h. R115777 administered orally twice daily for 10 consecutive days to mice bearing established s.c. MCF-7 xenografts induced tumor inhibition at a dose of 25 mg/kg [percentage of treated vs. control (% T/C) = 63% at day 21]. Greater inhibition was obsd. at doses of 50 mg/kg (% T/C at day 21 = 38%) or 100 mg/kg (% T/C at day 21 = 43%). The antitumor effect appeared to be mainly cytostatic with little evidence of tumor shrinkage to less than the starting vol. Tumor response correlated with an increase in the appearance of prelamin A, but no changes in the prenylation of lamin B, heat-shock protein 40, or N-Ras were detectable. In addn., significant increases in apoptotic index and p21WAF1/CIP1 expression were obsd., concomitant with a decrease in proliferation as measured by Ki-67 staining. An increase in prelamin A was also obsd. in peripheral blood lymphocytes in a breast cancer patient who responded to R115777. These data show that R115777 possesses preclin. antitumor activity against human breast cancer and that the appearance of prelamin A may provide a sensitive and convenient pharmacodynamic marker of inhibition of prenylation and(or) response.
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    42. 42
      Sieprath, T., Corne, T. D., Nooteboom, M., Grootaert, C., Rajkovic, A., Buysschaert, B., Robijns, J., Broers, J. L., Ramaekers, F. C., Koopman, W. J., Willems, P. H., and De Vos, W. H. (2015) Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates Nucleus 6, 236– 246 DOI: 10.1080/19491034.2015.1050568
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      Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates
      Sieprath, Tom; Corne, Tobias D. J.; Nooteboom, Marco; Grootaert, Charlotte; Rajkovic, Andreja; Buysschaert, Benjamin; Robijns, Joke; Broers, Jos L. V.; Ramaekers, Frans C. S.; Koopman, Werner J. H.; Willems, Peter H. G. M.; De Vos, Winnok H.
      Nucleus (Philadelphia, PA, United States) (2015), 6 (3), 236-246CODEN: NPPUBC; ISSN:1949-1042. (Taylor & Francis, Inc.)
      The cell nucleus is structurally and functionally organized by lamins, intermediate filament proteins that form the nuclear lamina. Point mutations in genes that encode a specific subset of lamins, the A-type lamins, cause a spectrum of diseases termed laminopathies. Recent evidence points to a role for A-type lamins in intracellular redox homeostasis. To det. whether lamin A/C depletion and prelamin A accumulation differentially induce oxidative stress, we have performed a quant. microscopy-based anal. of reactive oxygen species (ROS) levels and mitochondrial membrane potential (Δψm) in human fibroblasts subjected to sustained siRNA-mediated knockdown of LMNA and ZMPSTE24, resp. We measured a highly significant increase in basal ROS levels and an even more prominent rise of induced ROS levels in lamin A/C depleted cells, eventually resulting in Δψm hyperpolarization and apoptosis. Depletion of ZMPSTE24 on the other hand, triggered a senescence pathway that was assocd. with moderately increased ROS levels and a transient Δψm depolarization. Both knockdowns were accompanied by an upregulation of several ROS detoxifying enzymes. Taken together, our data suggest that both persistent prelamin A accumulation and lamin A/C depletion elevate ROS levels, but to a different extent and with different effects on cell fate. This may contribute to the variety of disease phenotypes witnessed in laminopathies.
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    43. 43
      Rowinsky, E. K., Windle, J. J., and Von Hoff, D. D. (1999) Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development J. Clin. Oncol. 17, 3631– 3652 DOI: 10.1200/JCO.1999.17.11.3631
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      Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development
      Rowinsky, Eric K.; Windle, Jolene J.; Von Hoff, Daniel D.
      Journal of Clinical Oncology (1999), 17 (11), 3631-3652CODEN: JCONDN; ISSN:0732-183X. (Lippincott Williams & Wilkins)
      A review with 175 refs. Ras proteins are guanine nucleotide-binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approx. 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first-and most crit.-modification is the addn. of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biol. active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clin. evaluations of FTase inhibitors to det. the feasibility of administering them on dose schedules like those that portend optimal therapeutic indexes in preclin. studies. Because of the unique biol. aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.
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    44. 44
      Körner, C., Keklikoglou, I., Bender, C., Wörner, A., Münstermann, E., and Wiemann, S. (2013) MicroRNA-31 sensitizes human breast cells to apoptosis by direct targeting of protein kinase C epsilon (PKC epsilon) J. Biol. Chem. 288, 8750– 8761 DOI: 10.1074/jbc.M112.414128
      There is no corresponding record for this reference.
    45. 45
      Girardot, V., Rabilloud, T., Yoshida, M., Beppu, T., Lawrence, J. J., and Khochbin, S. (1994) Relationship between core histone acetylation and histone H1(0) gene activity Eur. J. Biochem. 224, 885– 892 DOI: 10.1111/j.1432-1033.1994.00885.x
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      Relationship between core histone acetylation and histone H10 gene activity
      Girardot, Valerie; Rabilloud, Thierry; Yoshida, Minoru; Beppu, Teruhiko; Lawrence, Jean-Jacques; Khochbin, Saadi
      European Journal of Biochemistry (1994), 224 (3), 885-92CODEN: EJBCAI; ISSN:0014-2956.
      In this study we show a striking correlation between histone H10 gene expression and histone acetylation. Trichostatin A, a highly specific inhibitor of histone deacetylase, efficiently induces H10 gene expression. Moreover, using a cell line sensitive to trichostatin A (FM3A) and a derived cell line selected for its resistance to this inhibitor (TR303), it is shown that the level of H10 gene expression is related to the extent of chromatin acetylation. After showing the S-phase-dependent activation of H10 gene expression, we demonstrate that hyperacetylation has a dominant effect on H10 gene expression, since it enhances the expression of the gene independent of the position of cells in the cell cycle. This response to deacetylase inhibitors is specific to H10, since it is not shared by other cell-cycle-dependent histone genes (h1 and H4). Finally, by transfection of trichostatin-A-resistant and trichostatin-A-sensitive cells with a plasmid contg. a H10 promoter, we show that the exogenous H10 promoter is also highly sensitive to trichostatin A treatment and that activation of transcription follows exactly the same pattern as activation of the endogenous gene. Histone acetylation may be used to modulate H10 gene activity and offers insight into a possible mechanism in which the developmentally regulated chromatin acetylation acts to potentiate H10 gene expression.
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    46. 46
      Kostova, N. N., Srebreva, L. N., Milev, A. D., Bogdanova, O. G., Rundquist, I., Lindner, H. H., and Markov, D. V. (2005) Immunohistochemical demonstration of histone H1(0) in human breast carcinoma Histochem. Cell Biol. 124, 435– 443 DOI: 10.1007/s00418-005-0052-6
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      Immunohistochemical demonstration of histone H10 in human breast carcinoma
      Kostova, Nora N.; Srebreva, Ljuba N.; Milev, Angel D.; Bogdanova, Olga G.; Rundquist, Ingemar; Lindner, Herbert H.; Markov, Dimiter V.
      Histochemistry and Cell Biology (2005), 124 (5), 435-443CODEN: HCBIFP; ISSN:0948-6143. (Springer)
      Histone H10 is a linker histone subvariant present in tissues of low proliferation rate. It is supposed to participate in the expression and maintenance of the terminal differentiation phenotype. The aim of this work was to study histone H10 distribution in human breast carcinoma and its relationship with the processes of proliferation and differentiation. Most of the cells in carcinomas of moderate and high level of differentiation expressed histone H10 including cells invading connective and adipose tissues. In low differentiated tumors, the no. of H10 expressing cells was considerably lower. Staining of myoepithelial cells, when seen, and of stromal fibroblasts was variable. The metastatic malignant cells in the lymph nodes also accumulated H10 but lymphocytes were always neg. All immunopos. malignant cells exhibited signs of polymorphism. Double H10/Ki-67 staining showed that the growth fraction in more differentiated tumors belonged to the H10-pos. cells, while in poorly differentiated carcinomas it also included a cell subpopulation not expressing H10. If expressed, p27Kip1 was always found in H10-pos. cells. These findings are inconsistent with the widespread view that histone H10 is expressed only in terminally differentiated cells. Rather, they suggest that the protein is expressed in cells in a prolonged intermitotic period irresp. of their level of differentiation. Double H10/Ki-67 immunostaining could be a useful tool in studying the growth fraction in tumors.
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    47. 47
      Varisli, L., Gonen-Korkmaz, C., Debelec-Butuner, B., Erbaykent-Tepedelen, B., Muhammed, H. S., Bogurcu, N., Saatcioglu, F., and Korkmaz, K. S. (2011) Ubiquitously expressed hematological and neurological expressed 1 downregulates Akt-mediated GSK3β signaling, and its knockdown results in deregulated G2/M transition in prostate cells DNA Cell Biol. 30, 419– 429 DOI: 10.1089/dna.2010.1128
      There is no corresponding record for this reference.
    48. 48
      Davis, T. A., Loos, B., and Engelbrecht, A. M. (2014) AHNAK: the giant jack of all trades Cell. Signalling 26, 2683– 2693 DOI: 10.1016/j.cellsig.2014.08.017
      48
      AHNAK: The giant jack of all trades
      Davis, T. A.; Loos, B.; Engelbrecht, A.-M.
      Cellular Signalling (2014), 26 (12), 2683-2693CODEN: CESIEY; ISSN:0898-6568. (Elsevier)
      A review. The nucleoprotein AHNAK is an unusual and somewhat mysterious scaffolding protein characterized by its large size of approx. 700 kDa. Several aspects of this protein remain uncertain, including its exact mol. function and regulation on both the gene and protein levels. Various studies have attempted to annotate AHNAK and, notably, protein interaction and expression analyses have contributed greatly to our current understanding of the protein. The implicated biol. processes are, however, very diverse, ranging from a role in the formation of the blood-brain barrier, cell architecture and migration, to the regulation of cardiac calcium channels and muscle membrane repair. In addn., recent evidence suggests that AHNAK might be yet another accomplice in the development of tumor metastasis. This review will discuss the different functional roles of AHNAK, highlighting recent advancements that have added foundation to the proposed roles while identifying ties between them. Implications for related fields of research are noted and suggestions for future research that will assist in unravelling the function of AHNAK are offered.
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    49. 49
      Caruso, J. A. and Stemmer, P. M. (2011) Proteomic profiling of lipid rafts in a human breast cancer model of tumorigenic progression Clin. Exp. Metastasis 28, 529– 540 DOI: 10.1007/s10585-011-9389-5
      49
      Proteomic profiling of lipid rafts in a human breast cancer model of tumorigenic progression
      Caruso, Joseph A.; Stemmer, Paul M.
      Clinical & Experimental Metastasis (2011), 28 (6), 529-540CODEN: CEXMD2; ISSN:0262-0898. (Springer)
      Tumor biomarkers assist in the early detection of cancer, act as therapeutic targets for intervention, and function as diagnostic indicators for the evaluation of therapeutic responses. To identify novel human breast cancer biomarkers, we have analyzed the protein content of lipid rafts isolated from a series of human mammary epithelial cell lines with increasing tumorigenic potential. Since lipid rafts function as platforms for protein interaction crit. to several biol. processes, we hypothesized that the abundance of proteins assocd. with proliferation, invasion and metastasis would be dysregulated in highly transformed cells. For this purpose, the MCF10A epithelial lineage, which include benign MCF10A cells, premalignant AT and TG3B cells, and malignant CA1a tumor cells, was utilized. Detergent-resistant membranes were isolated from each line and proteins were identified and relatively quantitated using iTRAQ reagents and tandem mass spectrometry. 57 Proteins were identified, and 1667 peptide identifications, mapping to 49 proteins, contained sufficient information for semi-quant. anal. When comparing malignant to benign cells, we obsd. consistent alterations in groups of proteins, such as a 5.7-fold av. decrease in G protein content (n = 5), 2.7-fold decrease in glycosylphosphatidylinositol-linked proteins (n = 7) and 3.3-fold increase in intermediate filaments (n = 9). Several of the identified proteins, including caveolin-1, filamin A, keratins 5, 6 and 17, and vimentin, are bona fide or candidate biomarkers in clin. studies, underscoring the usefulness of the MCF10A series as a model to better understand the biol. mechanisms underlying cancer progression.
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    50. 50
      Yoshimaru, T., Ono, M., Bando, Y., Chen, Y. A., Mizuguchi, K., Shima, H., Komatsu, M., Imoto, I., Izumi, K., Honda, J., Miyoshi, Y., Sasa, M., and Katagiri, T. (2017) A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells Nat. Commun. 8, 15427 DOI: 10.1038/ncomms15427
      50
      A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells
      Yoshimaru, Tetsuro; Ono, Masaya; Bando, Yoshimi; Chen, Yi-An; Mizuguchi, Kenji; Shima, Hiroshi; Komatsu, Masato; Imoto, Issei; Izumi, Keisuke; Honda, Junko; Miyoshi, Yasuo; Sasa, Mitsunori; Katagiri, Toyomasa
      Nature Communications (2017), 8 (), 15427CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      Approx. 70% of breast cancer cells express estrogen receptor alpha (ERα). Previous studies have shown that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex has a crucial role in these cells. However, it remains unclear how BIG3 regulates the suppressive activity of PHB2. Here we demonstrate that BIG3 functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and the α isoform of the catalytic subunit of protein phosphatase 1 (PP1Cα), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and -S1208 serves to enhance PP1Cα activity, resulting in E2/ERα signalling activation via PHB2 inactivation due to PHB2-S39 dephosphorylation. Furthermore, an anal. of independent cohorts of ERα-pos. breast cancers patients reveal that both BIG3 overexpression and PHB2-S39 dephosphorylation are strongly assocd. with poor prognosis. This is the first demonstration of the mechanism of E2/ERα signalling activation via the BIG3-PKA-PP1Cα tri-complex in breast cancer cells.
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    51. 51
      Paget, J. A., Restall, I. J., Daneshmand, M., Mersereau, J. A., Simard, M. A., Parolin, D. A., Lavictoire, S. J., Amin, M. S., Islam, S., and Lorimer, I. A. (2012) Repression of cancer cell senescence by PKCι Oncogene 31, 3584– 3596 DOI: 10.1038/onc.2011.524
      There is no corresponding record for this reference.
    52. 52
      Paul, A., Gunewardena, S., Stecklein, S. R., Saha, B., Parelkar, N., Danley, M., Rajendran, G., Home, P., Ray, S., Jokar, I., Vielhauer, G. A., Jensen, R. A., Tawfik, O., and Paul, S. (2014) PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis Cell Death Differ. 21, 1469– 1481 DOI: 10.1038/cdd.2014.62
      52
      PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis
      Paul, A.; Gunewardena, S.; Stecklein, S. R.; Saha, B.; Parelkar, N.; Danley, M.; Rajendran, G.; Home, P.; Ray, S.; Jokar, I.; Vielhauer, G. A.; Jensen, R. A.; Tawfik, O.; Paul, S.
      Cell Death & Differentiation (2014), 21 (9), 1469-1481CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)
      Triple-neg. breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional anal. in exptl. mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly assocd. with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We obsd. that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a therapeutic option for breast cancer, including the TNBC subtype.
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    53. 53
      Vaysse, C., Philippe, C., Martineau, Y., Quelen, C., Hieblot, C., Renaud, C., Nicaise, Y., Desquesnes, A., Pannese, M., Filleron, T., Escourrou, G., Lawson, M., Rintoul, R. C., Delisle, M. B., Pyronnet, S., Brousset, P., Prats, H., and Touriol, C. (2015) Key contribution of eIF4H-mediated translational control in tumor promotion Oncotarget 6, 39924– 39940 DOI: 10.18632/oncotarget.5442
      There is no corresponding record for this reference.
    54. 54
      Hong, S. M., Park, C. W., Kim, S. W., Nam, Y. J., Yu, J. H., Shin, J. H., Yun, C. H., Im, S. H., Kim, K. T., Sung, Y. C., and Choi, K. Y. (2016) NAMPT suppresses glucose deprivation-induced oxidative stress by increasing NADPH levels in breast cancer Oncogene 35, 3544– 3554 DOI: 10.1038/onc.2015.415
      There is no corresponding record for this reference.
    55. 55
      Liu, X., Daskal, I., and Kwok, S. C. (2003) Effects of PTX1 expression on growth and tumorigenicity of the prostate cancer cell line PC-3 DNA Cell Biol. 22, 469– 474 DOI: 10.1089/104454903322247343
      There is no corresponding record for this reference.
    56. 56
      Browne, B. C., Hochgräfe, F., Wu, J., Millar, E. K., Barraclough, J., Stone, A., McCloy, R. A., Lee, C. S., Roberts, C., Ali, N. A., Boulghourjian, A., Schmich, F., Linding, R., Farrow, L., Gee, J. M., Nicholson, R. I., O’Toole, S. A., Sutherland, R. L., Musgrove, E. A., Butt, A. J., and Daly, R. J. (2013) Global characterization of signalling networks associated with tamoxifen resistance in breast cancer FEBS J. 280, 5237– 5257 DOI: 10.1111/febs.12441
      There is no corresponding record for this reference.
    57. 57
      Wang, W. H., Childress, M. O., and Geahlen, R. L. (2014) Syk interacts with and phosphorylates nucleolin to stabilize Bcl-x(L) mRNA and promote cell survival Mol. Cell. Biol. 34, 3788– 3799 DOI: 10.1128/MCB.00937-14
      57
      Syk interacts with and phosphorylates nucleolin to stabilize Bcl-xL mRNA and promote cell survival
      Wang, Wen-Horng; Childress, Michael O.; Geahlena, Robert L.
      Molecular and Cellular Biology (2014), 34 (20), 3788-3799, 13 pp.CODEN: MCEBD4; ISSN:1098-5549. (American Society for Microbiology)
      The Syk protein tyrosine kinase, a well-characterized regulator of immune cell function, plays an increasingly recognized role in tumorigenesis as a promoter of cell survival in both hematol. and nonhematol. malignancies. We show here that the expression of Syk in MCF7 or MDA-MB-231 breast cancer cells or in DG75 B-lymphoma cells protects cells from apoptosis induced by oxidative or genotoxic stress by stabilizing the mRNA for Bcl-xL, an antiapoptotic protein. Syk binds robustly to nucleolin and phosphorylates it on tyrosine, enhancing its ability to bind the Bcl-xL mRNA. Consequently, reducing the level of nucleolin by RNA interference attenuates the ability of Syk to protect cells from stress-induced cell death.
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    58. 58
      Christensen, L. L., Holm, A., Rantala, J., Kallioniemi, O., Rasmussen, M. H., Ostenfeld, M. S., Dagnaes-Hansen, F., Øster, B., Schepeler, T., Tobiasen, H., Thorsen, K., Sieber, O. M., Gibbs, P., Lamy, P., Hansen, T. F., Jakobsen, A., Riising, E. M., Helin, K., Lubinski, J., Hagemann-Madsen, R., Laurberg, S., Ørntoft, T. F., and Andersen, C. L. (2014) Functional screening identifies miRNAs influencing apoptosis and proliferation in colorectal cancer PLoS One 9, e96767 DOI: 10.1371/journal.pone.0096767
      There is no corresponding record for this reference.
    59. 59
      Nakakido, M., Tamura, K., Chung, S., Ueda, K., Fujii, R., Kiyotani, K., and Nakamura, Y. (2016) Phosphatidylinositol glycan anchor biosynthesis, class X containing complex promotes cancer cell proliferation through suppression of EHD2 and ZIC1, putative tumor suppressors Int. J. Oncol. 49, 868– 876 DOI: 10.3892/ijo.2016.3607
      59
      Phosphatidylinositol glycan anchor biosynthesis, class X containing complex promotes cancer cell proliferation through suppression of EHD2 and ZIC1, putative tumor suppressors
      Nakakido, Makoto; Tamura, Kenji; Chung, Suyoun; Ueda, Koji; Fujii, Risa; Kiyotani, Kazuma; Nakamura, Yusuke
      International Journal of Oncology (2016), 49 (3), 868-876CODEN: IJONES; ISSN:1791-2423. (Spandidos Publications Ltd.)
      We identified phosphatidylinositol glycan anchor biosynthesis, class X (PIGX), which plays a crit. role in the biosynthetic pathway of glycosylphosphatidylinositol (GPI)-anchor motif, to be upregulated highly and frequently in breast cancer cells. Knockdown of PIGX as well as reticulocalbin 1 (RCN1) and reticulocalbin 2 (RCN2), which we found to interact with PIGX and was indicated to regulate calcium-dependent activities, significantly suppressed the growth of breast cancer cells. We also identified PIGX to be a core protein in an RCN1/PIGX/RCN2 complex. Microarray anal. revealed that the expression of two putative tumor suppressor genes, Zic family member 1 (ZIC1) and EH-domain contg. 2 (EHD2), were upregulated commonly in cells in which PIGX, RCN1, or RCN2 was knocked down, suggesting that this RCN1/PIGX/RCN2 complex could neg. regulate the expression of these two genes and thereby contribute to human breast carcinogenesis. Our results imply that PIGX may be a good candidate mol. for development of novel anticancer drugs for breast cancer.
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    60. 60
      Sareen, D., Darjatmoko, S. R., Albert, D. M., and Polans, A. S. (2007) Mitochondria, calcium, and calpain are key mediators of resveratrol-induced apoptosis in breast cancer Mol. Pharmacol. 72, 1466– 1475 DOI: 10.1124/mol.107.039040
      There is no corresponding record for this reference.
    61. 61
      Gong, B., Hu, H., Chen, J., Cao, S., Yu, J., Xue, J., Chen, F., Cai, Y., He, H., and Zhang, L. (2013) Caprin-1 is a novel microRNA-223 target for regulating the proliferation and invasion of human breast cancer cells Biomed. Pharmacother. 67, 629– 636 DOI: 10.1016/j.biopha.2013.06.006
      61
      Caprin-1 is a novel microRNA-223 target for regulating the proliferation and invasion of human breast cancer cells
      Gong, Bo; Hu, Heyu; Chen, Jia; Cao, Shuang; Yu, Jing; Xue, Jianxiang; Chen, Fuhua; Cai, Ye; He, Hong; Zhang, Lei
      Biomedicine & Pharmacotherapy (2013), 67 (7), 629-636CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
      MicroRNAs (miRNAs) are 21-22 nucleotides regulatory small non-coding RNAs that inhibit gene expression by binding to complementary sequences esp. the 3' untranslated region (3'UTR) of mRNA. One miRNA can target many mRNAs, leading to a complex metabolic network. Previous studies have shown that miRNA-223 regulates migration and invasion of tumor cells and targets cytoplasmic activation/proliferation-assocd. protein-1 (Caprin-1). In the present study, we detected the expression of miRNA-223 and Caprin-1 in MCF-7, T-47D and MDA-MB-231 cancer cell lines, and MCF-10A normal breast cell line, and analyzed the role of miRNA-223 in Caprin-1-induced proliferation and invasion of human breast cancer cells. We found that miRNA-223 expression levels are significantly lower in MCF-7, T-47D and MDA-MB-231 cancer cells than in MCF-10A normal breast cells, while Caprin-1 expression is higher in cancer cells than in normal breast cells. The most malignant cancer cell line MDA-MB-231 has the lowest expression of miR-223, but the highest expression of Caprin-1. Further, we found that miR-223 targets the 3'UTR of Caprin-1 miRNA and down-regulates the expression of Caprin-1. We also found that over-expression of Caprin-1 can promote the proliferation and the invasion of breast cancer cells, but miRNA-223 can inhibit the proliferation and the invasion. miRNA-223-induced inhibition can be reversed by ectopic over-expression of Caprin-1. These findings suggest that miR-223 may suppress the proliferation and invasion of cancer cells by directly targeting Caprin-1. Our study also indicates that expression levels of miR-223 and Caprin-1 can be used to predict the state of cancer in breast cancer patient.
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    62. 62
      Rajan, R., Karbowniczek, M., Pugsley, H. R., Sabnani, M. K., Astrinidis, A., and La-Beck, N. M. (2015) Quantifying autophagosomes and autolysosomes in cells using imaging flow cytometry Cytometry, Part A 87, 451– 458 DOI: 10.1002/cyto.a.22652
      62
      Quantifying autophagosomes and autolysosomes in cells using imaging flow cytometry
      Rajan, Robin; Karbowniczek, Magdalena; Pugsley, Haley R.; Sabnani, Manoj K.; Astrinidis, Aristotelis; La-Beck, Ninh M.
      Cytometry, Part A (2015), 87 (5), 451-458CODEN: CPAYAV; ISSN:1552-4922. (Wiley-Blackwell)
      Autophagy dysregulation has been implicated in numerous diseases and many therapeutic agents are known to modulate this pathway. Therefore, the ability to accurately monitor autophagy is crit. to understanding its role in the pathogenesis and treatment of many diseases. Recently an imaging flow cytometry method measuring colocalization of microtubule assocd. protein 1B light chain 3 (LC3) and lysosomal signals via Bright Detail Similarity (BDS) was proposed which enabled evaluation of autophagic processing. However, since BDS only evaluates colocalization of LC3 and lysosomal signals, the no. of autophagy organelles was not taken into account. We found that in cells classified as having Low BDS, there was a large degree of variability in accumulation of autophagosomes. Therefore, we developed a new approach wherein BDS was combined with no. of LC3+ puncta, which enabled us to distinguish between cells having very few autophagy organelles vs. cells with accumulation of autophagosomes or autolysosomes. Using this method, we were able to distinguish and quantify autophagosomes and autolysosomes in breast cancer cells cultured under basal conditions, with inhibition of autophagy using chloroquine, and with induction of autophagy using amino acid starvation. This technique yields addnl. insight into autophagy processing making it a useful supplement to current techniques. © 2015 International Society for Advancement of Cytometry.
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    63. 63
      Hendershot, L. M. (2004) The ER function BiP is a master regulator of ER function Mt. Sinai J. Med. 71, 289– 297
      63
      The ER function BiP is a master regulator of ER function
      Hendershot Linda M
      The Mount Sinai journal of medicine, New York (2004), 71 (5), 289-97 ISSN:0027-2507.
      The endoplasmic reticulum (ER) is a command center of the cell that is second only to the nucleus in terms of the breadth of its influence on other organelles and activities. It is a major site of protein synthesis, contains the cellular calcium stores that are an essential component of many signaling pathways, and is the proximal site of a signal transduction cascade that responds to cellular stress conditions and serves to maintain homeostasis of the cell. All eucaryotic cells possess an ER, which can comprise nearly 50% of the membranes of a cell. Its functions can be divided into those that occur on the cytosolic side of the membrane (where protein translation and signal transduction cascades occur) and the luminal space (where most other ER functions take place). Our studies during the past several years have revealed that the ER molecular chaperone BiP is a master regulator of ER function. It is responsible for maintaining the permeability barrier of the ER during protein translocation, directing protein folding and assembly, targeting misfolded proteins for retrograde translocation so they can be degraded by the proteasome, contributing to ER calcium stores, and sensing conditions of stress in this organelle, to activate the mammalian unfolded protein response.
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    64. 64
      Hou, S., Isaji, T., Hang, Q., Im, S., Fukuda, T., and Gu, J. (2016) Distinct effects of β1 integrin on cell proliferation and cellular signaling in MDA-MB-231 breast cancer cells Sci. Rep. 6, 18430 DOI: 10.1038/srep18430
      64
      Distinct effects of β1 integrin on cell proliferation and cellular signaling in MDA-MB-231 breast cancer cells
      Hou, Sicong; Isaji, Tomoya; Hang, Qinglei; Im, Sanghun; Fukuda, Tomohiko; Gu, Jianguo
      Scientific Reports (2016), 6 (), 18430CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
      An aberrant expression of integrin β1 has been implicated in breast cancer progression. Here, we compared the cell behaviors of wild-type (WT), β1 gene deleted (KO), and β1 gene restored (Res) MDA-MB-231 cells. Surprisingly, the expression of β1 exhibited opposite effects on cell proliferation. These effects were dependent on cell densities, and they showed an up-regulation of cell proliferation when cells were cultured under sparse conditions, and a down-regulation of cell growth under dense conditions. By comparison with WT cells, the phosphorylation levels of ERK in KO cells were consistently suppressed under sparse culture conditions, but consistently up-regulated under dense culture conditions. The phosphorylation levels of EGFR were increased in the KO cells. By contrast, the phosphorylation levels of AKT were decreased in the KO cells. The abilities for both colony and tumor formation were significantly suppressed in the KO cells, suggesting that β1 plays an important role in cell survival signaling for tumorigenesis. These aberrant phenotypes in the KO cells were rescued in the Res cells. Taken together, these results clearly showed the distinct roles of β1 in cancer cells: the inhibition of cell growth and the promotion of cell survival, which may shed light on cancer therapies.
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    65. 65
      Hu, Y., Sun, Z., Deng, J., Hu, B., Yan, W., Wei, H., and Jiang, J. (2017) Splicing factor hnRNPA2B1 contributes to tumorigenic potential of breast cancer cells through STAT3 and ERK1/2 signaling pathway Tumor Biol. 39, 101042831769431 DOI: 10.1177/1010428317694318
      There is no corresponding record for this reference.
    66. 66
      Belizzi, A., Greco, M. R., Rubino, R., Paradiso, A., Forciniti, S., Zeeberg, K., Cardone, R. A., and Reshkin, S. J. (2015) The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells Int. J. Oncol. 46, 1214– 1224 DOI: 10.3892/ijo.2014.2805
      There is no corresponding record for this reference.
    67. 67
      Genovese, G., Ghosh, P., Li, H., Rettino, A., Sioletic, S., Cittadini, A., and Sgambato, A. (2012) The tumor suppressor HINT1 regulates MITF and β-catenin transcriptional activity in melanoma cells Cell Cycle 11, 2206– 2215 DOI: 10.4161/cc.20765
      67
      The tumor suppressor HINT1 regulates MITF and β-catenin transcriptional activity in melanoma cells
      Genovese, Giannicola; Ghosh, Papia; Li, Haiyang; Rettino, Alessando; Sioletic, Stefano; Cittadini, Achille; Sgambato, Alessandro
      Cell Cycle (2012), 11 (11), 2206-2215CODEN: CCEYAS; ISSN:1538-4101. (Landes Bioscience)
      Histidine triad nucleotide-binding protein 1 (HINT1) is a haploinsufficient tumor suppressor gene that inhibits the Wnt/β-catenin pathway in colon cancer cells and Microphthalmia-assocd. transcription factor (MITF) activity in human mast cells. MITF and β-catenin play a central role in melanocyte and melanoma cell survival, and this study aimed to investigate the effects of HINT1 on the MITF and β-catenin pathways in malignant melanoma cells. We found that HINT1 inhibits MITF and β-catenin transcriptional activity, and both proteins can be co-immunopptd. with an anti-HINT1-specific antibody in melanoma cell lines. Stable, constitutive overexpression of the HINT1 protein in human melanoma cells significantly impaired cell proliferation in vitro and tumorigenesis in vivo. These effects were assocd. with a decreased expression of cyclin D1 and BCL2, well known MITF and β-catenin transcription targets, resp. We also demonstrated that BCL2 and cyclin D1 can partially rescue the HINT1-driven phenotype. Moreover, we found in ChIP assays that HINT1 binds the chromatin at MITF and β-catenin sites in BCL2 and cyclin D1 promoters, resp., and that mSIN3a and HDAC1, well known transcriptional repressors, can be co-immunopptd. with an anti-HINT1-specific antibody. These findings support the tumor suppressor activity of HINT1 gene in melanoma cells by promoting the formation of non-functional complexes with oncogenic transcription factors like MITF and β-catenin.
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    68. 68
      Verdel, A. and Khochbin, S. (1999) Identification of a new family of higher eukaryotic histone deacetylases. Coordinate expression of differentiation-dependent chromatin modifiers J. Biol. Chem. 274, 2440– 2445 DOI: 10.1074/jbc.274.4.2440
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      Identification of a new family of higher eukaryotic histone deacetylases Coordinate expression of differentiation-dependent chromatin modifiers
      Verdel, Andre; Khochbin, Saadi
      Journal of Biological Chemistry (1999), 274 (4), 2440-2445CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      The histone deacetylase domain of almost all members of higher eukaryotic histone deacetylases already identified (HDAC family) is highly homologous to that of yeast RPD3. In this paper we report the cloning of two cDNAs encoding members of a new family of histone deacetylase in mouse that show a better homol. to yeast HDA1 histone deacetylase. These cDNAs encode relatively large proteins, presenting an in vitro trichostatin A-sensitive histone deacetylase activity. Interestingly, one, mHDA2, encodes a protein with two putative deacetylase domains, and the other, mHDA1, contains only one deacetylase homol. domain, located at the C-terminal half of the protein. Our data showed that these newly identified genes could belong to a network of genes coordinately regulated and involved in the remodeling of chromatin during cell differentiation. Indeed, the expression of mHDA1 and mHDA2 is tightly linked to the state of cell differentiation, behaving therefore like the histone H1° -encoding gene. Moreover, like histone H1° gene, mHDA1 and mHDA2 gene expression is induced upon deacetylase inhibitor treatment. We postulate the existence of a regulatory mechanism, commanding a coordinate expression of a group of genes involved in the remodeling of chromatin not only during cell differentiation but also after abnormal histone acetylation.
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    69. 69
      Tong, A., Zhang, H., Li, Z., Gou, L., Wang, Z., Wei, H., Tang, M., Liang, S., Chen, L., Huang, C., and Wei, Y. (2008) Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid Cancer Chemother. Pharmacol. 61, 791– 802 DOI: 10.1007/s00280-007-0536-2
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      Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid
      Tong, Aiping; Zhang, Haiyuan; Li, Zhengyu; Gou, Lantu; Wang, Zhi; Wei, Haiyan; Tang, Minghai; Liang, Shufang; Chen, Lijuan; Huang, Canhua; Wei, Yuquan
      Cancer Chemotherapy and Pharmacology (2008), 61 (5), 791-802CODEN: CCPHDZ; ISSN:0344-5704. (Springer)
      Purpose: Suberonylanilide hydroxamic acid (SAHA) is an orally administered histone deacetylase inhibitor (HDACI) that has shown significant antitumor activity in a variety of tumor cells. To evaluate if SAHA has an activity against liver cancer, and with an aim to identify the altered cellular factors upon SAHA treatment, human HepG2 cancer cell line was used as a model, and proteomic approach was utilized to elucidate the mol. mechanisms underlying SAHA's antitumor activity. Methods: Cell growth inhibition was measured by MTT method, and apoptosis was detected by means of flow cytometry anal. and TUNEL assay. Protein expression profiles were analyzed by 2-DE coupled with MALDI-Q-TOF MS/MS anal. Results: A total of 55 differentially expressed proteins were visualized by 2-DE and Coomassie Brilliant Blue (CBB) staining. Of these, 34 proteins were identified via MS/MS anal. Among the identified proteins, six proteins also displayed significant expression changes at earlier time points upon SAHA treatment, and such alterations were further confirmed by semi-quant. RT-PCR. Together, at both the mRNA and protein levels, SAHA suppressed the expression of reticulocalbin 1 precursor (RCN1), annexin A3 (ANXA3) and heat shock 27 kDa protein 1 (HSP27), while increasing the expression of aldose reductase (AR), triosephosphate isomerase 1 (TPI) and manganese superoxide dismutase (SOD2). Conclusion: SAHA remarkably inhibited proliferation of HepG2 cancer cells, and induced apoptosis in vitro. Using proteomics approaches, a variety of differentially expressed proteins were identified in HepG2 cancer cells before and after treatment with SAHA. This study will enable a better understanding of the mol. mechanisms underlying SAHA-mediated antitumor effects at the protein level.
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    70. 70
      Baumeister, P., Dong, D., Fu, Y., and Lee, A. S. (2009) Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis Mol. Cancer Ther. 8, 1086– 1094 DOI: 10.1158/1535-7163.MCT-08-1166
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      Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis
      Baumeister, Peter; Dong, Dezheng; Fu, Yong; Lee, Amy S.
      Molecular Cancer Therapeutics (2009), 8 (5), 1086-1094CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
      Histone deacetylase (HDAC) inhibitors are emerging as effective therapies in the treatment of cancer, and the role of HDACs in the regulation of promoters is rapidly expanding. GRP78/BiP is a stress inducible endoplasmic reticulum (ER) chaperone with antiapoptotic properties. We present here the mechanism for repression of the Grp78 promoter by HDAC1. Our studies reveal that HDAC inhibitors specifically induce GRP78, and the induction level is amplified by ER stress. Through mutational anal., we have identified the minimal Grp78 promoter and specific elements responsible for HDAC-mediated repression. We show the involvement of HDAC1 in the neg. regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275 but also by exogenous overexpression and small interfering RNA knockdown of specific HDACs. We present the results of chromatin immunopptn. anal. that reveals the binding of HDAC1 to the Grp78 promoter before, but not after, ER stress. Furthermore, overexpression of GRP78 confers resistance to HDAC inhibitor-induced apoptosis in cancer cells, and conversely, suppression of GRP78 sensitizes them to HDAC inhibitors. These results define HDAC inhibitors as new agents that upregulate GRP78 without concomitantly inducing the ER or heat shock stress response, and suppression of GRP78 in tumors may provide a novel, adjunctive option to enhance anticancer therapies that use these compds.
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    71. 71
      Juengel, E., Meyer dos Santos, S., Schneider, T., Makarevic, J., Hudak, L., Bartsch, G., Haferkamp, A., Wiesner, C., and Blaheta, R. A. (2013) HDAC inhibition suppresses bladder cancer cell adhesion to collagen under flow conditions Exp. Biol. Med. (London, U. K.) 238, 1297– 1304 DOI: 10.1177/1535370213498975
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      HDAC inhibition suppresses bladder cancer cell adhesion to collagen under flow conditions
      Juengel, Eva; Meyer dos Santos, Sascha; Schneider, Tanja; Makarevic, Jasmina; Hudak, Lukasz; Bartsch, Georg; Haferkamp, Axel; Wiesner, Christoph; Blaheta, Roman A.
      Experimental Biology and Medicine (London, United Kingdom) (2013), 238 (11), 1297-1304CODEN: EBMMBE; ISSN:1535-3699. (Sage Publications Ltd.)
      The influence of the histone deacetylase (HDAC)-inhibitor, valproic acid (VPA), on bladder cancer cell adhesion in vitro was investigated in this paper. TCCSUP and RT-112 bladder cancer cells were treated with VPA (0.5 or 1 mM) twice or thrice weekly for 14 days. Controls remained untreated. Tumor cell interaction with immobilized collagen was evaluated by a flow-based adhesion assay using a shear force of 2 or 4 dyne/cm2. The effects of VPA on the integrin adhesion receptors α3, α5, β1, β3 and β4 were assessed by flow cytometry to det. integrin surface expression and by western blotting to det. the cytoplasmic integrin level. VPA of 0.5mM and 1mM significantly prevented binding of both RT-112 and TCCSUP cells to collagen, compared with the untreated controls. Adhesion was reduced to a higher extent when RT-112 (subjected to 2dyne/cm2)or TCCSUP (subjected to 2 or 4 dyne/cm2) tumor cells were treated with VPA three times a week, compared to the two times a week protocol. VPA caused a significant up-regulation of the integrin α3, α5, β1, β3 and β4 subtypes on the TCCSUP cell surface membrane. In RT-112 cells, only integrin α5 was elevated on the cell surface following VPA exposure. Western blotting revealed an up-regulation of α3, α5, β3 and β4 integrins and down-regulation of the integrin β1 protein by VPA in TCCSUP. VPA also up-regulated α5 and down-regulated β1 integrin in RT-112 cells, but also reduced α3 and β3 in TCCSUP. VPA exerted adhesion-blocking properties on bladder cancer cells under physiol. flow conditions. The effects were accompanied by distinct modifications of the integrin expression profile, which differ depending on the cell lines used. Application of VPA might be an innovative option to prevent bladder cancer dissemination.
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    72. 72
      Dudakovic, A., Camilleri, E. T., Lewallen, E. A., McGee-Lawrence, M. E., Riester, S. M., Kakar, S., Montecino, M., Stein, G. S., Ryoo, H. M., Dietz, A. B., Westendorf, J. J., and van Wijnen, A. J. (2015) Histone deacetylase inhibition destabilizes the multi-potent state of uncommitted adipose-derived mesenchymal stromal cells J. Cell. Physiol. 230, 52– 62 DOI: 10.1002/jcp.24680
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      Histone Deacetylase Inhibition Destabilizes the Multi-Potent State of Uncommitted Adipose-Derived Mesenchymal Stromal Cells
      Dudakovic, Amel; Camilleri, Emily T.; Lewallen, Eric A.; McGee-Lawrence, Meghan E.; Riester, Scott M.; Kakar, Sanjeev; Montecino, Martin; Stein, Gary S.; Ryoo, Hyun-Mo; Dietz, Allan B.; Westendorf, Jennifer J.; van Wijnen, Andre J.
      Journal of Cellular Physiology (2015), 230 (1), 52-62CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)
      Human adipose-derived mesenchymal stromal cells (AMSCs) grown in platelet lysate are promising agents for therapeutic tissue regeneration. Here, we investigated whether manipulation of epigenetic events by the clin. relevant histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) alters differentiation of AMSCs. The multipotency of AMSCs was validated by their ability to differentiate into osteogenic, chondrogenic, and adipogenic lineages. High-throughput RNA sequencing and RT-qPCR established that human histone deacetylases (HDAC1 to HDAC11, and SIRT1 to SIRT7) are differentially expressed in AMSCs. SAHA induces hyper-acetylation of histone H3 and H4, stimulates protein expression of the HDAC-responsive gene SLC9A3R1/NHERF1 and modulates the AKT/FOXO1 pathway. Biol., SAHA interferes with osteogenic, chondrogenic and adipogenic lineage commitment of multipotent AMSCs. Mechanistically, SAHA-induced loss of differentiation potential of uncommitted AMSCs correlates with multiple changes in the expression of principal transcription factors that control mesenchymal or pluripotent states. We propose that SAHA destabilizes the multi-potent epigenetic state of uncommitted human AMSCs by hyper-acetylation and perturbation of key transcription factor pathways. Furthermore, AMSCs grown in platelet lysate may provide a useful biol. model for screening of new HDAC inhibitors that control the biol. fate of human mesenchymal stromal cells. J. Cell. Physiol. 229: 52-62, 2014. © 2014 Wiley Periodicals, Inc.
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