Maintenance of constitutive IκB kinase activity by glycogen synthase kinase-3α/β in pancreatic cancer

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