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

Oncogene volume 27, pages 499–505 (2008)Cite this article

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.

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Acknowledgements

We thank Dr AF Parlow of the National Hormone and Peptide Program, NIDDK for providing us with the recombinant human H2-relaxin and Dr ZJ Sun (Stanford University) for pcDNA3.1-β-catenin plasmid construction. The present work is supported by NIH and DOD grants to HJK and RWD. We acknowledge the support of CCSG (Cancer Center Support Grant) to UC Davis Cancer Center.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, School of Medicine and Cancer Center, University of California, Sacramento, CA, USA

    S Liu, C Tepper, A-H Ma, L-Y Wang, L D Fitzgerald, Z Wu & H-J Kung

  2. Department of Urology, School of Medicine and Cancer Center, University of California, Sacramento, CA, USA

    R L Vinall, X-B Shi, L R Xue & R W deVere White

  3. Department of Pathology, School of Medicine and Cancer Center, University of California, Sacramento, CA, USA

    R Gandour-Edwards

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  1. S Liu
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Correspondence to R W deVere White or H-J Kung.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Liu, S., Vinall, R., Tepper, C. et al. Inappropriate activation of androgen receptor by relaxin via β-catenin pathway. Oncogene 27, 499–505 (2008). https://doi.org/10.1038/sj.onc.1210671

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