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GSK-3? promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-?B.

ABSTRACT: Mutations in KRAS drive the oncogenic phenotype in a variety of tumors of epithelial origin. The NF-?B transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently, TGF-?-activated kinase 1 (TAK1), an upstream regulator of I?B kinase (IKK), which controls canonical NF-?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? (GSK-3?), leading to its interaction with TAK1 to stabilize the TAK1-TAB complex to promote IKK activity. In addition, GSK-3? is required for promoting critical noncanonical NF-?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? as a key downstream effector of oncogenic KRAS via its ability to coordinately regulate distinct NF-?B signaling pathways.


PROVIDER: S-EPMC3679268 | BioStudies | 2013-01-01

REPOSITORIES: biostudies

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