Inappropriate activation of androgen receptor by relaxin via beta-catenin pathway.
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.
Liu
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S
Department of Biochemistry and Molecular Medicine, School of Medicine and Cancer Center, University of California, Sacramento, CA, USA.
Vinall
R L
RL
Tepper
C
C
Shi
X-B
XB
Xue
L R
LR
Ma
A-H
AH
Wang
L-Y
LY
Fitzgerald
L D
LD
Wu
Z
Z
Gandour-Edwards
R
R
deVere White
R W
RW
Kung
H-J
HJ
D002467:Cell Nucleus / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012065:Relaxin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; C095068:RLN2 protein, human; D011944:Receptors, Androgen; D051176:beta Catenin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012065:Relaxin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D017430:Prostate-Specific Antigen