Distinct expression and activity of GSK-3α and GSK-3β in prostate cancer

Darrington, R.S., Campa, V.M., Walker, M.M., Bengoa-Vergniory, N., Gorrono-Etxebarria, I., Uysal Onganer, P., Kawano, Y., Waxman, J. and Kypta, R.M. 2012. Distinct expression and activity of GSK-3α and GSK-3β in prostate cancer. International Journal of Cancer. 131 (6), p. E872–E883. doi:10.1002/ijc.27620

TitleDistinct expression and activity of GSK-3α and GSK-3β in prostate cancer
AuthorsDarrington, R.S., Campa, V.M., Walker, M.M., Bengoa-Vergniory, N., Gorrono-Etxebarria, I., Uysal Onganer, P., Kawano, Y., Waxman, J. and Kypta, R.M.
Abstract

Glycogen synthase kinase (GSK-3) is upregulated in many types of tumor, including prostate cancer. GSK-3 inhibitors reduce prostate tumor cell growth; however, it is not clear if both isoforms, GSK-3α and GSK-3β, are involved. Here, we compared their expression in prostate tumors and used gene silencing to study their functions in 22Rv1 prostate cancer cells. Compared to normal prostate, GSK-3α and GSK-3β were upregulated in 25/79 and 24/79 cases of prostate cancer, respectively, with GSK-3α elevated in low Gleason sum score tumors and GSK-3β expressed in high Gleason tumors, and both isoforms correlating with high expression of the androgen receptor (AR). Gene silencing of GSK-3α and, to a lesser extent, GSK-3β reduced AR transcriptional activity. In addition, silencing of GSK-3β, but not GSK-3α, reduced Akt phosphorylation. Acute and chronic silencing of either isoform reduced 22Rv1 growth in colony formation assays; however, this did not correlate with effects on AR activity. The GSK-3 inhibitor CHIR99021 reduced 22Rv1 colony formation by 50% in normal growth medium and by 15% in hormone-depleted medium, suggesting that GSK-3 is required both for hormone-dependent and hormone-independent proliferation. In addition, CHIR99021 enhanced growth inhibition by the AR antagonists bicalutamide and MDV3100. Finally, expression of GSK3A and GSK3B mRNAs correlated with a gene expression signature for androgen-regulated genes. Our observations highlight the importance of the GSK-3/AR signaling axis in prostate cancer and support the case for development of isoform-specific GSK-3 inhibitors and their use, in combination with AR antagonists, to treat patients with prostate cancer.

JournalInternational Journal of Cancer
Journal citation131 (6), p. E872–E883
ISSN0020-7136
Year2012
PublisherWiley
Digital Object Identifier (DOI)doi:10.1002/ijc.27620
Publication dates
Published15 Sep 2012

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