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

Piyan Zhang, Janet Schaefer-Klein, John C. Cheville, George Vasmatzis, Irina V. Kovtun

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)24428-24442
Number of pages15
JournalOncotarget
Volume9
Issue number36
DOIs
StatePublished - May 11 2018

Keywords

  • Delta catenin
  • Disease progression
  • Prostate cancer
  • Treatment

ASJC Scopus subject areas

  • Oncology

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