Abstract 1810: Heterogeneous activation of PP-1 and Akt determines AR-v7 protein expression in prostate cancer cells under AR inhibition

Abstract

Abstract Background: Blocking the androgen receptor (AR) signaling is the first- and second-line treatment for metastatic prostate cancers. Although the newly developed AR pathway inhibitor (ARPI) improves patient survival, tumors invariably recurs and are most often driven by reactivation of the AR signaling. Enhanced expression of the AR splice variant, AR-v7, had been demonstrated to be one of the key mechanisms that confer prostate tumors with therapy resistance. However, molecular mechanisms by which control AR-v7 protein expression remain unclear. Experimental Design: Multiple prostate cancer lines were challenged with androgen depletion and/or Enzalutamide treatment. Protein phosphatase-1 (PP-1) and Akt kinase activation were measured. AR and AR-v7 serine phosphorylation, ubiquitination, protein degradation as well as subcellular localization were determined. Results: Enzalutamide induces differential activation of protein phosphatase-1 (PP-1) and Akt kinase depending on the genetic background of prostate cancer cell lines. PP-1 activation prevents AR-v7 from serine213 phosphorylation, Mdm2-mediated ubiquitination modification, cytoplasmic localization and proteasomal protein degradation. By contrast, Akt activation functions in the opposite to PP-1 and stimulates AR-v7 degradation. Therefore, the balance of PP-1 and Akt activations under ARPI treatment determines AR-v7 protein expression in prostate cancer cells. Conclusion: Our studies highlight the decisive roles of PP-1 and Akt for AR-v7 protein expression and activities when AR is functionally blocked. It also provides an explanation on heterogeneous AR-v7 protein expression in prostate tumor biopsies. Citation Format: Yinan Li, Ning Xie, Martin E. Gleave, Paul Rennie, Xuesen Dong. Heterogeneous activation of PP-1 and Akt determines AR-v7 protein expression in prostate cancer cells under AR inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1810.