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Maintenance of Constitutive IB Kinase Activity by Glycogen Synthase Kinase-3/β in Pancreatic Cancer

Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina

Requests for reprints: Albert S. Baldwin, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, CB#7295, Chapel Hill, NC 27599-7295. Phone: 919-966-3652; Fax: 919-966-8212; E-mail: asbaldwin{at}med.unc.edu.

Key Words: Pancreatic cancer • glycogen synthase kinase-3 • IB kinase • NF-B

Constitutive nuclear factor B (NF-B) 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-3β (GSK-3β) plays a key role in maintaining basal NF-B target gene expression and cell survival in pancreatic cancer cell lines. However, the mechanism by which GSK-3β facilitates constitutive NF-B signaling in pancreatic cancer remains unclear. In this report, we analyze the contributions of both GSK-3 isoforms (GSK-3 and GSK-3β) in regulating NF-B 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-B DNA binding activity, transcriptional activity, and cell proliferation in Panc-1 and MiaPaCa-2 cells. Our data also indicate that IB kinase (IKK) subunits are not equally required to regulate pancreatic cancer–associated NF-B activity and cell growth. Importantly, we provide the first evidence that GSK-3 maintains constitutive NF-B signaling in pancreatic cancer by regulating IKK activity. These data provide new insight into GSK-3–dependent NF-B regulation and further establish GSK-3 and IKK as potential therapeutic targets for pancreatic cancer. [Cancer Res 2008;68(19):8156–63]