PD33-03 PHARMACOLOGIC TARGETING OF TGF-β MEDIATED EMT IN PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I1 Apr 2017PD33-03 PHARMACOLOGIC TARGETING OF TGF-β MEDIATED EMT IN PROSTATE CANCER Zheng Cao, Shahriar Koochekpour, Stephen Strup, and Natasha Kyprianou Zheng CaoZheng Cao More articles by this author , Shahriar KoochekpourShahriar Koochekpour More articles by this author , Stephen StrupStephen Strup More articles by this author , and Natasha KyprianouNatasha Kyprianou More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3317AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Dysregulation of transforming growth factor-β (TGF-β) and insulin-like growth factor (IGF) axis has been linked to reactive stroma dynamics in tumor microenvironment during prostate cancer progression. IGFBP3 induction is initiated by stroma remodeling and could represent a potential therapeutic target for prostate cancer treatment. A lead quinazoline-based Doxazosin® derivative, DZ-50, generated in our laboratory, inhibits prostate tumor growth and vascularity via inducing anoikis and disrupting focal adhesions. Molecular profiling revealed that process of epithelial-mesenchymal-transition (EMT) is also targeted by DZ-50. In this study, we investigated the effect of DZ-50 on EMT landscape, EMT to mesenchymal-epithelial-transition (MET) conversion, and migratory ability of prostate cancer cells within prostate tumor microenvironment. METHODS Human prostate cancer cells LNCaP, LNCaP overexpressing TGF-β type II receptor (TβRII), and cancer associated fibroblasts (CAFs) derived from human prostate cancer specimens, were used. Antitumor effect of DZ-50 against prostate cancer epithelial cells and CAFs was evaluated using cell viability assays. Effect of the drug on EMT key regulators (including IGFBP3) was determined using RT-PCR and Western blot analysis. Drug-induced phenotypic conversions of EMT were evaluated by confocal microscopy. Impact of TGF-β from the stroma microenvironment or exogenous addition of the cytokine, on migration of prostate tumor cells, was assessed using Matrigel assays. RESULTS DZ-50 induced cell death in prostate cancer epithelial cells and CAFs, in a concentration-dependent manner. DZ-50 downregulated IGFBP3 mRNA and protein expression and contributed to MET in LNCaP cells. DZ-50 decreased nuclear IGFBP3 expression with no effect on total protein and promoted MET in LNCaPTβRII cells. In addition, TGF-β reversed DZ-50-induced MET by upregulating IGFBP3 expression in LNCaPTβRII cells. Co-cultures of LNCaPTβRII with CAFs promoted prostate cancer cell migration via TGF-β, an effect that was inhibited by DZ-50. CONCLUSIONS Our results demonstrate that DZ-50 inhibits prostate cancer cell migration and invasion. DZ-50 caused reversal of EMT to MET by regulating IGFBP3 and potentially targeting the prostate stroma in tumor microenvironment. This evidence integrates new signaling mechanisms underlying the antitumor effect of DZ-50 and calls for pre-clinical studies to establish the therapeutic value of this compound in advanced metastatic prostate cancer. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e594 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Zheng Cao More articles by this author Shahriar Koochekpour More articles by this author Stephen Strup More articles by this author Natasha Kyprianou More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...