Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells.

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.

• Authors: Andrei V Ougolkov, Martin E Fernandez-Zapico, Doris N Savoy, Raul A Urrutia, Daniel D Billadeau
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 6 Pg. 2076-81 (Mar 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 15781615 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• NF-kappa B
• Thiazoles
• N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
• Urea
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Apoptosis (drug effects, physiology)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Cell Survival (physiology)
• Gene Expression Regulation, Neoplastic (drug effects, physiology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism, physiology)
• Glycogen Synthase Kinase 3 beta
• Humans
• NF-kappa B (physiology)
• Pancreatic Neoplasms (enzymology, genetics, pathology)
• Thiazoles (pharmacology)
• Transcription, Genetic (physiology)
• Urea (analogs & derivatives, pharmacology)