Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression

Authors

Bilal B. Hafeez, The University of Texas Rio Grande ValleyFollow
Aditya Ganju
Mohammed Sikander, The University of Texas Rio Grande Valley
Vivek K. Kashyap, The University of Texas Rio Grande Valley
Zubair Bin Hafeez
Neeraj Chauhan, The University of Texas Rio Grande Valley
Shabnam Malik, The University of Texas Rio Grande Valley
Andrew Massey
Manish Tripathi, The University of Texas Rio Grande Valley
Fathi T. Halaweish, South Dakota State University
Murali M. Yallapu, The University of Texas Rio Grande Valley
Subhash C. Chauhan, The University of Texas Rio Grande Valley
Meena Jaggi, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

10-2017

Abstract

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), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ormeloxifene showed proficient docking with β-catenin and GSK3β. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer 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, 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 μg/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 β-catenin and EMT pathway.

Comments

Original published version available at https://doi.org/10.1158/1535-7163.MCT-17-0157

Recommended Citation

Hafeez, B. B., Ganju, A., Sikander, M., Kashyap, V. K., Hafeez, Z. B., Chauhan, N., Malik, S., Massey, A. E., Tripathi, M. K., Halaweish, F. T., Zafar, N., Singh, M. M., Yallapu, M. M., Chauhan, S. C., & Jaggi, M. (2017). Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression. Molecular cancer therapeutics, 16(10), 2267–2280. https://doi.org/10.1158/1535-7163.MCT-17-0157

Publication Title

Molecular Cancer Therapeutics

DOI

10.1158/1535-7163.MCT-17-0157

Academic Level

faculty

Mentor/PI Department

Immunology and Microbiology