Ormeloxifene suppresses prostate tumor growth and metastatic phenotypes via inhibition of oncogenic β-catenin signaling and EMT progression

Published on Oct 1, 2017in Molecular Cancer Therapeutics5.615
· DOI :10.1158/1535-7163.MCT-17-0157
Bilal Bin Hafeez29
Estimated H-index: 29
(UT: University of Tennessee),
Aditya Ganju12
Estimated H-index: 12
(UT: University of Tennessee)
+ 12 AuthorsMeena Jaggi36
Estimated H-index: 36
(UT: University of Tennessee)
Ormeloxifene (ORM), is a clinically approved selective estrogen receptor modulator, which has also shown excellent anti-cancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ORM on prostate cancer (PrCa) and elucidate a novel molecular mechanism of its anti-cancer activity. ORM treatment inhibited epithelial to mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, and vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ORM showed proficient docking with β-catenin and GSK3β. In addition, ORM induced apoptosis, inhibited growth and metastatic potential of PrCa cells and arrested cell cycle in G0-G1 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, ORM remarkably reduced tumorigenic, migratory and invasive potential of PrCa cells. Additionally, ORM treatment significantly (P
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