title: Distinct expression and activity of GSK-3α and GSK-3β in prostate cancer.
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.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: R Siobhan
authors.initials: RS
authors.lastname: Darrington
authors.forename: Victor M
authors.initials: VM
authors.lastname: Campa
authors.forename: Marjorie M
authors.initials: MM
authors.lastname: Walker
authors.forename: Nora
authors.initials: N
authors.lastname: Bengoa-Vergniory
authors.forename: Irantzu
authors.initials: I
authors.lastname: Gorrono-Etxebarria
authors.forename: Pinar
authors.initials: P
authors.lastname: Uysal-Onganer
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawano
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waxman
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kypta
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D000726:Androgen Antagonists; D012333:RNA, Messenger; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha