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

5400 Glycogen synthase kinase 3s (GSK3s) reportedly has opposing roles, repressing Wnt/s-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-κB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3s in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3s 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 s-catenin oncoprotein in the tumor cells. Inhibition of GSK3s activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3s activity by chemical inhibitors and its expression by RNA interference targeting GSK3s induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3s 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 (Biochem Biophys Res Commun 2005;334:1365-73; Oncology 2007, in press; PCT/JP2006/300160).