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Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res 2005 Mar 15;65(6):2076-81 PMID: 15781615

Pubmed ID

15781615

Abstract

Recent studies using glycogen synthase kinase-3beta (GSK-3beta)-deficient mouse embryonic fibroblasts suggest that GSK-3beta positively regulates nuclear factor kappaB (NFkappaB)-mediated gene transcription. Because NFkappaB is suggested to participate in cell proliferation and survival pathways in pancreatic cancer, we investigated the role of GSK-3beta in regulating these cellular processes. Herein, we show that pancreatic cancer cells contain a pool of active GSK-3beta and that pharmacologic inhibition of GSK-3 kinase activity using small molecule inhibitors or genetic depletion of GSK-3beta by RNA interference leads to decreased cancer cell proliferation and survival. Mechanistically, we show that GSK-3beta influences NFkappaB-mediated gene transcription at a point distal to the Ikappa kinase complex, as only ectopic expression of the NFkappaB subunits p65/p50, but not an Ikappa kinase beta constitutively active mutant, could rescue the decreased cellular proliferation and survival associated with GSK-3beta inhibition. Taken together, our results simultaneously identify a previously unrecognized role for GSK-3beta in cancer cell survival and proliferation and suggest GSK-3beta as a potential therapeutic target in the treatment of pancreatic cancer.

Author List

Ougolkov AV, Fernandez-Zapico ME, Savoy DN, Urrutia RA, Billadeau DD

Author

Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-16844374033   228 Citations

MESH terms used to index this publication - Major topics in bold

Apoptosis
Cell Growth Processes
Cell Line, Tumor
Cell Survival
Gene Expression Regulation, Neoplastic
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Humans
NF-kappa B
Pancreatic Neoplasms
Thiazoles
Transcription, Genetic
Urea
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad