GSK-3alpha Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1-TAB Stabilization and Regulation of Non-Canonical NF-kB
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ABSTRACT: Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways
ORGANISM(S): Homo sapiens
PROVIDER: GSE42559 | GEO | 2013/05/31
SECONDARY ACCESSION(S): PRJNA182550
REPOSITORIES: GEO
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