1. Frequently rearranged and overexpressed δ-catenin is responsible for low sensitivity of prostate cancer cells to androgen receptor and β-catenin antagonists
- Author
-
George Vasmatzis, Piyan Zhang, Janet Schaefer-Klein, John C. Cheville, and Irina V. Kovtun
- Subjects
0301 basic medicine ,treatment ,Cell growth ,Chemistry ,Wnt signaling pathway ,delta catenin ,prostate cancer ,medicine.disease ,Androgen receptor ,03 medical and health sciences ,Prostate cancer ,disease progression ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Catenin Delta-2 ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,Catenin ,Cancer research ,medicine ,Delta catenin ,Research Paper - 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, δ-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 δ-catenin overexpression. We find that δ-catenin in PCa cells exists in a complex with E-cadherin, p120, and α- and β-catenin. Increased expression of δ-catenin leads to its further stabilization as well as upregulation and stabilization of its binding partners. Resistant to degradation and overexpressed δ-catenin isoform activates Wnt signaling pathway by increasing the level of nuclear β-catenin and subsequent stimulation of Tcf/Lef transcription targets. Evaluation of responses to treatments, with androgen receptor (AR) antagonist and β-catenin inhibitors revealed that cells with high levels of δ-catenin are more resistant to killing with single agent treatment than matched control cells. We show that combination treatment targeting both AR and β-catenin networks is more effective in suppressing tumor growth than targeting a single network. In conclusion, targeting clinically significant PCa with high levels of δ–catenin with anti-androgen and anti β-catenin combination therapy may prevent progression of the disease to a castration-resistant state and, thus, represents a promising therapeutic strategy.
- Published
- 2018