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Targeting Dependency on the GPX4 Lipid Peroxide Repair Pathway for Cancer Therapy
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Biochemistry

Cite this: Biochemistry 2018, 57, 14, 2059–2060
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https://doi.org/10.1021/acs.biochem.8b00307
Published March 27, 2018

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Cells are dependent on their lipid composition for establishing and modulating membrane structural integrity, morphology, metabolism, and other cellular functions. For example, among the thousands of lipid species that compose eukaryotic cell membranes, the abundance and localization of polyunsaturated fatty acid (PUFA)-containing phospholipids (PUFA-PLs) are major factors in determining the fluidity of cell membranes. (1) Because the cis conformation of double bonds in PUFAs hinders efficient stacking of these fatty acid tails, elevated levels of PUFA-PLs contribute to increasing membrane fluidity and thinning.
PUFAs are, however, susceptible to lipid peroxidation via reaction with molecular oxygen at bis-allylic positions, catalyzed by lipoxygenases or through non-enzymatic mechanisms. Oxygenated PUFAs can serve as lipid signals, regulating inflammatory processes, for example. However, peroxy-PUFAs are prone to decompose into reactive species, which can damage biomolecules, such as proteins and nucleic acids. Thus, cells depend on a critical network of proteins to repair PUFA-PL peroxides. A key protein at the center of this repair network is the selenoprotein glutathione peroxidase 4 (GPX4); it is the only peroxidase in mammals capable of reducing phospholipid hydroperoxides within cell membranes.
When GPX4 activity is compromised, lipid peroxidation can cause ferroptosis, an oxidative iron-dependent form of non-apoptotic cell death. Ferroptosis has been implicated in degenerative diseases; for example, ferroptosis inhibitors are protective in models of Parkinson’s, Huntington’s and Alzheimer’s diseases. (2) On the other hand, ferroptosis induced by exogenous agents is selectively lethal toward tumor cells that are addicted to GPX4 repair activity, which has suggested that inducing ferroptosis may be a beneficial approach to treating some cancers. (2,3)
Cancer cells from tissues of diverse origins have been screened for their sensitivity to ferroptosis-inducing compounds. (3) Ferroptosis inducers, including GPX4 inhibitors, were found to selectively target cancers with a mesenchymal or otherwise drug-resistant signature. Consistent with the mesenchymal state being associated with drug resistance, another study on persister cancer cells, which are proposed to escape from conventional cytotoxic treatment through a dormant state and then revive to cause tumor relapse, revealed a similar selective dependency on the GPX4 pathway. (4) Indeed, GPX4 inhibitors were among the compounds most selectively lethal to such persister cells.
Examination of persister cells revealed upregulation of mesenchymal markers and downregulation of epithelial markers. This common mesenchymal character partially explained the extension of GPX4 dependency from high-mesenchymal cancers to persister cells; the underlying mechanisms of GPX4 dependency remain to be further illuminated (Figure 1).

Figure 1

Figure 1. Cancer cells undergo EMT to acquire resistance to apoptosis induction and chemotherapy. EMT requires an elevated level of PUFA-PLs, which inevitably makes cancer cells vulnerable to lipid peroxidation and ferroptosis induced by GPX4 inhibition.

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Overexpression of mesenchymal state genes is associated with epithelial–mesenchymal transition (EMT). Because EMT increases the motility of tumor cells and enables the invasion of a primary tumor to distant sites, EMT is part of the process of metastasis. EMT also renders cancer cells resistant to apoptosis and chemotherapy. (5) EMT requires plasma membrane remodeling to increase fluidity, which is associated with an elevated level of biosynthesis of PUFA-PLs. Given that PUFAs are more susceptible to peroxidation than saturated or monounsaturated fatty acid PLs are, cells in an EMT state should be more dependent on GPX4 to control lipid peroxides. Therefore, cancer cells undergoing EMT that acquire resistance to apoptosis induction may inevitably become vulnerable to lipid peroxidation and ferroptosis induced by GPX4 inhibition. The necessity of the EMT regulator and lipogenic factor ZEB1 for GPX4 dependency and sensitivity to fatty acid desaturase-2 (FADS2) activation support this theory. (3) The disabled antioxidant program in persister cells might be a result of this overwhelming lipid oxidation, considering that recycling of GPX4 consumes reduced glutathione (GSH) and NADPH. (4) Additionally, therapy-resistant cancer cells with a high-mesenchymal state due to a mesenchymal origin may exhibit similar genetic alterations and protein expression, explaining their vulnerability to ferroptosis.

Therapeutic Possibilities

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As cancer cells can evolve into a high-mesenchymal or related drug-resistant state and become resistant to apoptosis induction, one may be able to selectively target such resistant cancer cells through ferroptosis induction. The most effective compounds in this context might be direct GPX4 inhibitors. For example, in vivo xenografts of GPX4-knockout high-mesenchymal therapy-resistant melanoma regressed after the cessation of ferrostatin-1 (a lipophilic antioxidant that suppresses the effect of loss of GPX4) and did not relapse after dabrafenib and trametinib treatment had been ceased, while GPX4 wild-type xenografts continued to grow in both experiments. (3)
However, because the gpx4 gene is essential for embryonic development and some adult tissue homeostasis in mice, there is a concern about the potential toxicity of the therapeutic use of GPX4 inhibitors. However, GPX4 inhibitors were selectively lethal to persister cancer cells, with a minimal effect on parental cells and nontransformed cells, suggesting that the addiction to GPX4 may create a suitable therapeutic window. Despite this, the therapeutic window of the GPX4 inhibitor remains to be examined, such as its potential adverse impact on the nervous system and kidney in particular.
In addition to GPX4 direct inhibitors, persister cells might also be vulnerable to other ferroptosis inducers. For example, erastin and its derivatives, which inhibit system xc- and deplete the intracellular GPX4 cofactor GSH, are also selectively lethal to persister cancer cells, with minimal effects on parental cells. Additionally, high-mesenchymal state cancers are sensitive to statins, which can inhibit the biosynthesis of GPX4 and deplete mevalonate-derived coenzyme Q10. Although tumors might develop other resistance mechanisms for compounds such as erastin and statins, the high potential therapeutic index may be useful: for example, knockout of the system xc- gene slc7A11 has minimal effects in mice, suggesting that normal tissues do not require system xc- activity, at least in mice.
Dependency on GPX4 may thus derive from elevated levels of synthesis and usage of PUFA-PLs by some cancer cells, particularly the most drug-resistant and aggressive types. Further experiments that aimed to examine this lipid metabolism pathway may reveal additional therapeutic targets with different profiles. The GPX4 pathway thus represents a new frontier in targeting some of the most intractable cancers.

Author Information

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  • Corresponding Authors
    • Stuart L. Schreiber,  Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States;  Broad Institute, Cambridge, Massachusetts 02142, United States,  Orcidhttp://orcid.org/0000-0003-1922-7558,  Email: [email protected]
    • Brent R. Stockwell,  Department of Chemistry, Columbia University, New York, New York 10027, United States;  Department of Biological Sciences, Columbia University, 550 West 120th Street, MC 4846, New York, New York 10027, United States,  Orcidhttp://orcid.org/0000-0002-3532-3868,  Email: [email protected]
  • Author
  • Funding

    The research of the authors is supported by the National Cancer Institute and the National Institutes of Health (Grants R35CA209896 and P01CA087497 to B.R.S. and Grants GM038627 and U01CA176152 to S.L.S.).

  • Notes
    The authors declare no competing financial interest.

References

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Cite this: Biochemistry 2018, 57, 14, 2059–2060
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https://doi.org/10.1021/acs.biochem.8b00307
Published March 27, 2018

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  • Abstract

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    Figure 1

    Figure 1. Cancer cells undergo EMT to acquire resistance to apoptosis induction and chemotherapy. EMT requires an elevated level of PUFA-PLs, which inevitably makes cancer cells vulnerable to lipid peroxidation and ferroptosis induced by GPX4 inhibition.

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  • References

    This article references 5 other publications.

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      A review. Modern lipidomics anal. paints a dynamic picture of membrane organizations, as changing and adapting lipid assemblies that play an active role in cellular function. This article highlights how the lipid compn. of membranes dets. specific organelle functions, how homeostatic mechanisms maintain these functions by regulating phys. properties of membranes, and how cells disrupt lipid homeostasis to bring about regulated cell death (RCD). These are broad phenomena, and representative examples are reviewed here. In particular, the mechanisms of ferroptosis - a form of RCD brought about by lipid peroxidn. - are highlighted, demonstrating how lipid metab. drives cells' lipid compn. toward states of increased sensitivity to lipid oxidn. An understanding of these interactions has begun to give rise to lipid-based therapies. This article reviews current successes of such therapies, and suggests directions for future developments.
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      A review. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsatd. fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biol. processes, including amino acid, iron, and polyunsatd. fatty acid metab., and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathol. cell death assocd. with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biol. and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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      Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway
      Viswanathan, Vasanthi S.; Ryan, Matthew J.; Dhruv, Harshil D.; Gill, Shubhroz; Eichhoff, Ossia M.; Seashore-Ludlow, Brinton; Kaffenberger, Samuel D.; Eaton, John K.; Shimada, Kenichi; Aguirre, Andrew J.; Viswanathan, Srinivas R.; Chattopadhyay, Shrikanta; Tamayo, Pablo; Yang, Wan Seok; Rees, Matthew G.; Chen, Sixun; Boskovic, Zarko V.; Javaid, Sarah; Huang, Cherrie; Wu, Xiaoyun; Tseng, Yuen-Yi; Roider, Elisabeth M.; Gao, Dong; Cleary, James M.; Wolpin, Brian M.; Mesirov, Jill P.; Haber, Daniel A.; Engelman, Jeffrey A.; Boehm, Jesse S.; Kotz, Joanne D.; Hon, Cindy S.; Chen, Yu; Hahn, William C.; Levesque, Mitchell P.; Doench, John G.; Berens, Michael E.; Shamji, Alykhan F.; Clemons, Paul A.; Stockwell, Brent R.; Schreiber, Stuart L.
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      Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state obsd. in human tumors and cancer cell lines has been assocd. with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsatd. lipids. These lipids are the substrates for lipid peroxidn. by lipoxygenase enzymes. This lipid metab. creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-contg. enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFaqt73P&md5=10a709dd6ddcb1f55da583cd0f33e065
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      Nature (London, United Kingdom) (2017), 551 (7679), 247-250CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for nonmutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumors may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumor relapse. The authors previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here the authors show that a similar therapy-resistant cell state underlies the behavior of persister cells derived from a wide range of cancers and drug treatments. Consequently, the authors demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumor relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslehur3P&md5=abf1573029d2beebda41be4c3b477b57
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      Fischer, K. R. (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472– 476,  DOI: 10.1038/nature15748
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      Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance
      Fischer, Kari R.; Durrans, Anna; Lee, Sharrell; Sheng, Jianting; Li, Fuhai; Wong, Stephen T. C.; Choi, Hyejin; El Rayes, Tina; Ryu, Seongho; Troeger, Juliane; Schwabe, Robert F.; Vahdat, Linda T.; Altorki, Nasser K.; Mittal, Vivek; Gao, Dingcheng
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      The role of epithelial-to-mesenchymal transition (EMT) in metastasis is a longstanding source of debate, largely owing to an inability to monitor transient and reversible EMT phenotypes in vivo. Here we establish an EMT lineage-tracing system to monitor this process in mice, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models. We show that within a predominantly epithelial primary tumor, a small proportion of tumor cells undergo EMT. Notably, lung metastases mainly consist of non-EMT tumor cells that maintain their epithelial phenotype. Inhibiting EMT by overexpressing the microRNA miR-200 does not affect lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment owing to reduced proliferation, apoptotic tolerance and increased expression of chemoresistance-related genes. Overexpression of miR-200 abrogated this resistance. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVajs7%252FM&md5=438be17af02f54142f5cfefe4300ec8e