Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation.
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.
Shakoori
Abbas
A
Division of Diagnostic Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.
Ougolkov
Andrei
A
Yu
Zhi Wei
ZW
Zhang
Bin
B
Modarressi
Mohammad H
MH
Billadeau
Daniel D
DD
Mai
Masayoshi
M
Takahashi
Yutaka
Y
Minamoto
Toshinari
T
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
C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3