AR-v7 protein expression is regulated by protein kinase and phosphatase

// Yinan Li 1 , Ning Xie 1 , Martin E. Gleave 1 , Paul S. Rennie 1 and Xuesen Dong 1 1 Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada Correspondence to: Xuesen Dong, email: // Keywords : castration resistant prostate cancer, AR-v7, serine phosphorylation, protein stability, PP-1 and Akt Received : August 04, 2015 Accepted : August 27, 2015 Published : September 10, 2015 Abstract Failure of androgen-targeted therapy and progression of castration-resistant prostate cancer (CRPC) are often attributed to sustained expression of the androgen receptor (AR) and its major splice variant, AR-v7. Although the new generation of anti-androgens such as enzalutamide effectively inhibits AR activity, accumulating pre-clinical and clinical evidence indicates that AR-v7 remains constitutively active in driving CRPC progression. However, molecular mechanisms which control AR-v7 protein expression remain unclear. We apply multiple prostate cancer cell models to demonstrate that enzalutamide induces differential activation of protein phosphatase-1 (PP-1) and Akt kinase depending on the gene context of cancer cells. The balance between PP-1 and Akt activation governs AR phosphorylation status and activation of the Mdm2 ubiquitin ligase. Mdm2 recognizes phosphorylated serine 213 of AR-v7, and induces AR-v7 ubiquitination and protein degradation. These findings highlight the decisive roles of PP-1 and Akt for AR-v7 protein expression and activities when AR is functionally blocked.