Metformin Represses Androgen-dependent And Androgen-independent Prostate Cancers By Targeting Androgen Receptor

Background:Metformin has been reported to inhibit the growth of different types of cancers, including prostate cancer. We were interested to understand if the effect of metformin on prostate cancer is AR-dependent and, if so, whether metformin could act synergistically with the other anti-AR agents to serve as a therapeutic regimen with high efficacy and low toxicity.Methods:Cell viabilities and apoptosis were determined by MTT assay and annexin V-FITC staining, respectively, when the two human prostate cancer cell lines, the androgen-dependent LNCa P and the androgen-independent 22RV1 were treatment with metformin alone or in combination with bicalutamide. Quantitative RT-PCR and western blotting assays were conducted to exam metformin effects on AR m RNA and protein levels, respectively. Chromatin immunoprecipitation(Ch IP) assays were conducted to confirm the recruitment of AR to the ARE(s) located on the promoter region of the AR target gene PSA.Results:Metformin treatment reduced cell viability and enhanced apoptosis for both cell lines and synergistic effects between metformin and bicalutamide were observed in LNCaP cells. Metformin down-regulated full-length AR protein in LNCaP cells; both full-length and the truncated AR(AR-v7) were down-regulated by metformin in CWR22Rv1 cells. In both LNCa P and CWR22Rv1 cells, metformin repressed AR signaling pathway not by affecting AR protein degradation/stability, but rather through down-regulating the levels of AR mRNAs.Conclusions:Metformin represses prostate cancer cell viability and enhances apoptosis by targeting the AR signaling pathway. Combinations of metformin and other anti-AR agents pose a potentially promising therapeutic approach for treatment of prostate cancers, especially the castrate-resistant prostate cancer, with high efficacy and low toxicity.