Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth.
The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which is beta-catenin. Interest in the role of beta-catenin in prostate cancer has been stimulated by reports showing that it is aberrantly expressed in the cytoplasm and/or nucleus in up to 38% of hormone-refractory tumours and that overexpression of beta-catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenous beta-catenin on AR activity using Axin and RNA interference. Axin, which promotes beta-catenin degradation, inhibited AR transcriptional activity. However, this did not require the beta-catenin-binding domain of Axin. Depletion of beta-catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenous beta-catenin is not a transcriptional coactivator for the AR. The glycogen synthase kinase-3 (GSK-3)-binding domain of Axin prevented formation of a GSK-3-AR complex and was both necessary and sufficient for inhibition of AR-dependent transcription. A second GSK-3-binding protein, FRAT, also inhibited AR transcriptional activity, as did the GSK-3 inhibitors SB216763 and SB415286. Finally, inhibition of GSK-3 reduced the growth of AR-expressing prostate cancer cell lines. Our observations suggest a potential new therapeutic application for GSK-3 inhibitors in prostate cancer.
Mazor
Michal
M
Prostate Cancer Research Group, Department of Cancer Cell Biology, Division of Medicine, Imperial College, London W12 0NN, UK.
Kawano
Yoshiaki
Y
Zhu
Hanneng
H
Waxman
Jonathan
J
Kypta
Robert M
RM
D000627:Aminophenols / Q000494:pharmacology; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008969:Molecular Sequence Data; D011089:Polydeoxyribonucleotides; D011471:Prostatic Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D015534:Trans-Activators / Q000502:physiology; D051176:beta Catenin
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011089:Polydeoxyribonucleotides; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C417521:SB 216763; D015534:Trans-Activators; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3