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Distinct expression and activity of GSK‐3α and GSK‐3β in prostate cancer
Author(s) -
Darrington R. Siobhan,
Campa Victor M.,
Walker Marjorie M.,
BengoaVergniory Nora,
GorronoEtxebarria Irantzu,
UysalOnganer Pinar,
Kawano Yoshiaki,
Waxman Jonathan,
Kypta Robert M.
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27620
Subject(s) - prostate cancer , gene silencing , cancer research , protein kinase b , gsk 3 , prostate , lncap , androgen receptor , chemistry , cancer , biology , medicine , endocrinology , kinase , signal transduction , gene , microbiology and biotechnology , biochemistry
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.