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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Chem. Biol. 2011, 6, 5, 452-465
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Identification and Optimization of Small Molecules That Restore E-Cadherin Expression and Reduce Invasion in Colorectal Carcinoma Cells

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†Department of Pharmacology, ‡Department of Surgery, §Vanderbilt Institute of Chemical Biology, ∥Department of Cancer Biology, Department of Cell and Developmental Biology, and ⊥Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37215, United States
Department of Veterans Affairs, Tennessee Valley Healthcare System
*[email protected]
Cite this: ACS Chem. Biol. 2011, 6, 5, 452–465
Publication Date (Web):January 18, 2011
https://doi.org/10.1021/cb100305h
Copyright © 2011 American Chemical Society
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Abstract

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E-cadherin is a transmembrane protein that maintains intercellular contacts and cell polarity in epithelial tissue. The down-regulation of E-cadherin contributes to the induction of the epithelial-to-mesenchymal transition (EMT), resulting in an increased potential for cellular invasion of surrounding tissues and entry into the bloodstream. Loss of E-cadherin has been observed in a variety of human tumors as a result of somatic mutations, chromosomal deletions, silencing of the CDH1 gene promoter, and proteolytic cleavage. To date, no compounds directly targeting E-cadherin restoration have been developed. Here, we report the development and use of a novel high-throughput immunofluorescent screen to discover lead compounds that restore E-cadherin expression in the SW620 colon adenocarcinoma cell line. We confirmed restoration of E-cadherin using immunofluorescent microscopy and were able to determine the EC50 for selected compounds using an optimized In-Cell Western assay. The profiled compounds were also shown to have a minimal effect on cell proliferation but did decrease cellular invasion. We have also conducted preliminary investigations to elucidate a discrete molecular target to account for the phenotypic behavior of these small molecules and have noted a modest increase in E-cadherin mRNA transcripts, and RNA-Seq analysis demonstrated that potent analogues elicited a 10-fold increase in CDH1 (E-cadherin) gene expression.

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