Deregulated GSK3β activity in colorectal cancer:: Its association with tumor cell survival and proliferation

Glycogen synthase kinase 3 beta (GSK3 beta) reportedly has opposing roles, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-kappa B pathway on the other. The present investigation was undertaken to clarify the roles of GSK3 beta in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3 beta expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of beta-catenin oncoprotein in the tumor cells. Inhibition of GSK3 beta activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3 beta activity by chemical inhibitors and its expression by RNA interference targeting GSK3 beta induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3 beta in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer. (c) 2005 Elsevier Inc. All rights reserved.