title: Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation.
abstract: Glycogen synthase kinase 3beta (GSK3beta) reportedly has opposing roles, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-kappaB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3beta in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3beta 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 GSK3beta activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3beta activity by chemical inhibitors and its expression by RNA interference targeting GSK3beta induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3beta 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.
authors.affiliation: Division of Diagnostic Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.
authors.forename: Abbas
authors.initials: A
authors.lastname: Shakoori
authors.forename: Andrei
authors.initials: A
authors.lastname: Ougolkov
authors.forename: Zhi Wei
authors.initials: ZW
authors.lastname: Yu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Modarressi
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Toshinari
authors.initials: T
authors.lastname: Minamoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology*; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3