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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

Date

03/23/2005

Pubmed ID

15781615

DOI

10.1158/0008-5472.CAN-04-3642

Scopus ID

2-s2.0-16844374033 (requires institutional sign-in at Scopus site)   311 Citations

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




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