Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells.
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.[1]References
- Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Ougolkov, A.V., Fernandez-Zapico, M.E., Savoy, D.N., Urrutia, R.A., Billadeau, D.D. Cancer Res. (2005) [Pubmed]
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