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

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.

Oncotarget. 2015 Sep 10 [Epub ahead of print]

Yinan Li, Ning Xie, Martin E Gleave, Paul S Rennie, Xuesen Dong

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. , Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. , Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. , Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. , Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.

PubMed

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