Glycogen synthase kinase-3β participates in nuclear factor κB-mediated gene transcription and cell survival in pancreatic cancer cells

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