This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Cited by other online articles Google Scholar Articles by Ougolkov, A. V. Articles by Billadeau, D. D. Articles citing this Article Search for Related Content PubMed PubMed Citation Articles by Ougolkov, A. V. Articles by Billadeau, D. D.

Glycogen Synthase Kinase-3ß Participates in Nuclear Factor B–Mediated Gene Transcription and Cell Survival in Pancreatic Cancer Cells

¹ Division of Oncology Research and ² GI Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota

Requests for reprints: Daniel D. Billadeau, Mayo Clinic, Division of Oncology Research, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-266-4334; Fax: 507-266-5146; E-mail: billadeau.daniel{at}mayo.edu.

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

Key Words: GSK-3 • NF-B

This article has been cited by other articles: (Search Google Scholar for Other Citing Articles)

				M. Kunnimalaiyaan, A. M. Vaccaro, M. A. Ndiaye, and H. Chen Inactivation of glycogen synthase kinase-3{beta}, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells Mol. Cancer Ther., March 1, 2007; 6(3): 1151 - 1158. [Abstract] [Full Text] [PDF]

				E. Rodionova, M. Conzelmann, E. Maraskovsky, M. Hess, M. Kirsch, T. Giese, A. D. Ho, M. Zoller, P. Dreger, and T. Luft GSK-3 mediates differentiation and activation of proinflammatory dendritic cells Blood, February 15, 2007; 109(4): 1584 - 1592. [Abstract] [Full Text] [PDF]

				A. V. Ougolkov, M. E. Fernandez-Zapico, V. N. Bilim, T. C. Smyrk, S. T. Chari, and D. D. Billadeau Aberrant Nuclear Accumulation of Glycogen Synthase Kinase-3{beta} in Human Pancreatic Cancer: Association with Kinase Activity and Tumor Dedifferentiation Clin. Cancer Res., September 1, 2006; 12(17): 5074 - 5081. [Abstract] [Full Text] [PDF]

				X. Deng, D. Z. Ewton, S. Li, A. Naqvi, S. E. Mercer, S. Landas, and E. Friedman The Kinase Mirk/Dyrk1B Mediates Cell Survival in Pancreatic Ductal Adenocarcinoma. Cancer Res., April 15, 2006; 66(8): 4149 - 4158. [Abstract] [Full Text] [PDF]