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  • Title: Glycogen synthase kinase-3beta: a prognostic marker and a potential therapeutic target in human bladder cancer.
    Author: Naito S, Bilim V, Yuuki K, Ugolkov A, Motoyama T, Nagaoka A, Kato T, Tomita Y.
    Journal: Clin Cancer Res; 2010 Nov 01; 16(21):5124-32. PubMed ID: 20889919.
    Abstract:
    PURPOSE: Although recent studies have shown glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase, as a positive regulator of pancreatic, colon, and kidney cancer cell survival and proliferation, the role of GSK-3 in bladder cancer remains unknown. Our objectives were to determine the subcellular localization of GSK-3β and to evaluate the effect of GSK-3 inhibition in bladder cancer. EXPERIMENTAL DESIGN: We used immunohistochemical staining and nuclear/cytosolic fractionation to determine the expression pattern of GSK-3β in human urothelial carcinomas. To study the effect of GSK-3 inhibition on bladder cancer cell proliferation and survival, we used pharmacologic inhibitors of GSK-3, RNA interference, MTS assay, bromodeoxyuridine incorporation assay, quantitative reverse transcriptase-PCR, and Western blotting. RESULTS: We found aberrant nuclear accumulation of GSK-3β in 62% (43 of 69) and 91% (21 of 23) of noninvasive and invasive human urothelial carcinomas, respectively. GSK-3β nuclear staining was significantly associated with high-grade tumors (P < 0.001), advanced stage of bladder cancer (P < 0.05), metastasis (P < 0.05), and worse cause-specific survival (P < 0.05) in bladder cancer patients. Moreover, we found that pharmacologic inhibition or genetic depletion of GSK-3β resulted in decreased viability of bladder cancer cells. CONCLUSIONS: Our results suggest nuclear accumulation of GSK-3β as a novel prognostic marker in bladder cancer, show that GSK-3 contributes to urothelial cancer cell proliferation and survival, and identify GSK-3 as a potential therapeutic target in human bladder cancer.
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