Journal
MOLECULAR CANCER THERAPEUTICS
Volume 16, Issue 10, Pages 2267-2280Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-17-0157
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Funding
- Department of Defense (DOD) [W81XWH-14-1-0154]
- NIH [U01CA162106, R01CA142736]
- College of Pharmacy/University of Tennessee Health Science Center Seed grant
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Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), beta-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3 beta. In molecular docking analysis, ormeloxifene showed proficient docking with beta-catenin and GSK3 beta. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G(0)-G(1) phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly (P < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 mg/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving b-catenin and EMT pathway. (C) 2017 AACR.
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