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Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth

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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Acknowledgements

We thank Charlotte Bevan for pSG5 AR, Marc van de Wetering and Hans Clevers for pTER and pTERβi, Trevor Dale and Jonathan Franca-Koh for AX2, AX2P, FRAT constructs and GSK-3 constructs and Christopher Gregory for CWR-R1 cells. We are grateful to Maria Vivanco (Institute of Cancer Research, London) for comments on the manuscript. This work was supported by the Prostate Cancer Charity, UK.

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Correspondence to Robert M Kypta.

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Mazor, M., Kawano, Y., Zhu, H. et al. Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth. Oncogene 23, 7882–7892 (2004). https://doi.org/10.1038/sj.onc.1208068

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