Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth
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2004
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Abstract
The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which is β-catenin. Interest in the role of β-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 β-catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenous β-catenin on AR activity using Axin and RNA interference. Axin, which promotes β-catenin degradation, inhibited AR transcriptional activity. However, this did not require the β-catenin-binding domain of Axin. Depletion of β-catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenous β-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.
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mazor2004oncogeneinhibition
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| Authors | Michal Mazor;Yoshiaki Kawano;Hanneng Zhu;Jonathan Waxman;Robert M Kypta;Michal Mazor;Yoshiaki Kawano;Hanneng Zhu;Jonathan Waxman;Robert M Kypta; |
| Journal | Oncogene |
| Year | 2004 |
| DOI |
doi:10.1038/sj.onc.1208068
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