Frequently rearranged and overexpressed ?-catenin is responsible for low sensitivity of prostate cancer cells to androgen receptor and ?-catenin antagonists.

ABSTRACT: The mechanism of prostate cancer (PCa) progression towards the hormone refractory state remains poorly understood. Treatment options for such patients are limited and present a major clinical challenge. Previously, ?-catenin was reported to promote PCa cell growth in vitro and its increased level is associated with PCa progression in vivo. In this study we show that re-arrangements at Catenin Delta 2 (CTNND2) locus, including gene duplications, are very common in clinically significant PCa and may underlie ?-catenin overexpression. We find that ?-catenin in PCa cells exists in a complex with E-cadherin, p120, and ?- and ?-catenin. Increased expression of ?-catenin leads to its further stabilization as well as upregulation and stabilization of its binding partners. Resistant to degradation and overexpressed ?-catenin isoform activates Wnt signaling pathway by increasing the level of nuclear ?-catenin and subsequent stimulation of Tcf/Lef transcription targets. Evaluation of responses to treatments, with androgen receptor (AR) antagonist and ?-catenin inhibitors revealed that cells with high levels of ?-catenin are more resistant to killing with single agent treatment than matched control cells. We show that combination treatment targeting both AR and ?-catenin networks is more effective in suppressing tumor growth than targeting a single network. In conclusion, targeting clinically significant PCa with high levels of ?-catenin with anti-androgen and anti ?-catenin combination therapy may prevent progression of the disease to a castration-resistant state and, thus, represents a promising therapeutic strategy.

SUBMITTER: Zhang P 

PROVIDER: S-EPMC5966253 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature