GSK-3α Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1-TAB Stabilization and Regulation of Noncanonical NF-κB

Mutations in KRAS drive the oncogenic phenotype in a variety of tumors of epithelial origin. The NF-kappa B transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently, TGF-beta-activated kinase 1 (TAK1), an upstream regulator of I kappa B kinase (IKK), which controls canonical NF-kappa B signaling, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS-mutant colorectal cancer cell growth and survival. Here, we show that mutant KRAS upregulates glycogen synthase kinase 3 alpha (GSK-3 alpha), leading to its interaction with TAK1 to stabilize the TAK1-TAB complex to promote IKK activity. In addition, GSK-3 alpha is required for promoting critical noncanonical NF-kappa B signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with the loss of expression of oncogenic genes such as c-myc and TERT. These data identify GSK-3 alpha as a key downstream effector of oncogenic KRAS via its ability to coordinately regulate distinct NF-kappa B signaling pathways. SIGNIFICANCE: GSK-3 alpha functions to promote IKK/NF-kappa B activity downstream of oncogenic KRAS via stabilization and activation of the TAK1/TAB complex and to promote noncanonical NF-kappa B activity via control of nuclear levels of NF-kappa B2. Inhibition of GSK-3 strongly suppresses growth of human pancreatic tumor explants with downregulation of certain oncogenic NF-kappa B target genes such as c-myc and TERT. (c) 2013 AACR.