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- Title
Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth.
- Authors
Mazor, Michal; Kawano, Yoshiaki; Zhu, Hanneng; Waxman, Jonathan; Kypta, Robert M
- Abstract
The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which isß-catenin. Interest in the role ofß-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 ofß-catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenousß-catenin on AR activity using Axin and RNA interference. Axin, which promotesß-catenin degradation, inhibited AR transcriptional activity. However, this did not require theß-catenin-binding domain of Axin. Depletion ofß-catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenousß-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.Oncogene (2004) 23, 7882-7892. doi:10.1038/sj.onc.1208068 Published online 13 September 2004
- Subjects
GLYCOGEN; ENZYMES; ANDROGENS; PROSTATE cancer; CANCER cell growth; CANCER prevention; ONCOLOGY
- Publication
Oncogene, 2004, Vol 23, Issue 47, p7882
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1208068