Maintenance of constitutive IkappaB kinase activity by glycogen synthase kinase-3alpha/beta in pancreatic cancer.
Constitutive nuclear factor kappaB (NF-kappaB) activation is among the many deregulated signaling pathways that are proposed to drive pancreatic cancer cell growth and survival. Recent reports suggest that glycogen synthase kinase-3beta (GSK-3beta) plays a key role in maintaining basal NF-kappaB target gene expression and cell survival in pancreatic cancer cell lines. However, the mechanism by which GSK-3beta facilitates constitutive NF-kappaB signaling in pancreatic cancer remains unclear. In this report, we analyze the contributions of both GSK-3 isoforms (GSK-3alpha and GSK-3beta) in regulating NF-kappaB activation and cell proliferation in pancreatic cancer cell lines (Panc-1 and MiaPaCa-2). We show that GSK-3 isoforms are differentially required to maintain basal NF-kappaB DNA binding activity, transcriptional activity, and cell proliferation in Panc-1 and MiaPaCa-2 cells. Our data also indicate that IkappaB kinase (IKK) subunits are not equally required to regulate pancreatic cancer-associated NF-kappaB activity and cell growth. Importantly, we provide the first evidence that GSK-3 maintains constitutive NF-kappaB signaling in pancreatic cancer by regulating IKK activity. These data provide new insight into GSK-3-dependent NF-kappaB regulation and further establish GSK-3 and IKK as potential therapeutic targets for pancreatic cancer.
Wilson
Willie
W
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, USA. 27599-7295
Baldwin
Albert S
AS
D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000378:metabolism; D011485:Protein Binding; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D007527:Isoenzymes; D016328:NF-kappa B; D013844:Thiazoles; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051550:I-kappa B Kinase; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha