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

Andrei V. Ougolkov, Martin E. Fernandez-Zapico, Doris N. Savoy, Raul A. Urrutia, Daniel D. Billadeau

Research output: Contribution to journalArticle

246 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)2076-2081
Number of pages6
JournalCancer research
Volume65
Issue number6
DOIs
StatePublished - Mar 15 2005

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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