Glycogen Synthase Kinase-3β Participates in Nuclear Factor κB–Mediated Gene Transcription and Cell Survival in Pancreatic Cancer Cells
Open Access
- 15 March 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 65 (6), 2076-2081
- https://doi.org/10.1158/0008-5472.can-04-3642
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.Keywords
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This publication has 17 references indexed in Scilit:
- Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesisCancer Cell, 2005
- Genetic Deletion of Glycogen Synthase Kinase-3β Abrogates Activation of IκBα Kinase, JNK, Akt, and p44/p42 MAPK but Potentiates Apoptosis Induced by Tumor Necrosis FactorPublished by Elsevier BV ,2004
- Differential Regulation of TCR-mediated Gene Transcription by Vav Family MembersThe Journal of Experimental Medicine, 2004
- Structural Insights and Biological Effects of Glycogen Synthase Kinase 3-specific Inhibitor AR-A014418Journal of Biological Chemistry, 2003
- NKG2D-DAP10 triggers human NK cell–mediated killing via a Syk-independent regulatory pathwayNature Immunology, 2003
- Advanced Pancreatic Ductal Cancer: Fibrotic Focus and β-Catenin Expression Correlate With OutcomePancreas, 2003
- NF-κB as a therapeutic target in cancerTrends in Molecular Medicine, 2002
- Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from deathJournal of Neurochemistry, 2001
- Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicinOncogene, 2001
- Protein Kinase C and Calcineurin Synergize to Activate IκB Kinase and NF-κB in T LymphocytesPublished by Elsevier BV ,1999