Inappropriate activation of androgen receptor by relaxin via Β-catenin pathway

S. Liu, Ruth Louise Vinall, Clifford G Tepper, X. B. Shi, L. R. Xue, A. H. Ma, L. Y. Wang, L. D. Fitzgerald, Z. Wu, Regina F Gandour-Edwards, Ralph W deVere White, Hsing-Jien Kung

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

We have previously demonstrated that human H2-relaxin can mediate androgen-independent growth of LNCaP through a mechanism that involves the activation of the androgen receptor (AR) signaling pathway. The goal of the current study is to elucidate the mechanism(s) by which H2-relaxin causes activation of the AR pathway. Our data indicate that there is cross-talk between AR and components of the Wnt signaling pathway. Addition of H2-relaxin to LNCaP cells resulted in increased phosphorylation of protein kinase B (Akt) and inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β) with subsequent cytoplasmic accumulation of β-catenin. Immunoprecipitation and immunocytochemical studies demonstrated that the stabilized β-catenin formed a complex with AR, which was then translocated into the nucleus. Chromatin immunoprecipitation analysis determined that the AR/β-catenin complex binds to the proximal region of the prostate-specific antigen promoter. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, using LY294002, prevented both H2-relaxin-mediated phosphorylation of Akt and GSK-3β and translocation of β-catenin/AR into the nucleus. Knockdown of β-catenin levels using a β-catenin-specific small interfering RNA inhibited H2-relaxin-induced AR activity. The combined data demonstrate that PI3K/Akt and components of the Wnt pathway can facilitate H2-relaxin-mediated activation of the AR pathway.

Original languageEnglish (US)
Pages (from-to)499-505
Number of pages7
JournalOncogene
Volume27
Issue number4
DOIs
StatePublished - Jan 17 2008

Keywords

  • β-catenin
  • Androgen receptor
  • GPCR
  • H2-relaxin
  • Prostate cancer
  • Wnt

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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