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Inappropriate activation of androgen receptor by relaxin via beta-catenin pathway.

Research paper by S S Liu, R L RL Vinall, C C Tepper, X-B XB Shi, L R LR Xue, A-H AH Ma, L-Y LY Wang, L D LD Fitzgerald, Z Z Wu, R R Gandour-Edwards, R W RW deVere White, H-J HJ Kung

Indexed on: 27 Jul '07Published on: 27 Jul '07Published in: Oncogene



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-3beta (GSK-3beta) with subsequent cytoplasmic accumulation of beta-catenin. Immunoprecipitation and immunocytochemical studies demonstrated that the stabilized beta-catenin formed a complex with AR, which was then translocated into the nucleus. Chromatin immunoprecipitation analysis determined that the AR/beta-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-3beta and translocation of beta-catenin/AR into the nucleus. Knockdown of beta-catenin levels using a beta-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.