Oncotarget

Research Papers:

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

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

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:33743-33754. https://doi.org/10.18632/oncotarget.5608

Metrics: PDF 2068 views  |   HTML 1586 views  |   ?  


Abstract

Yinan Li1, Ning Xie1, Martin E. Gleave1, Paul S. Rennie1 and Xuesen Dong1

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 5608