GSK-3α promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-κB

Cancer Discov. 2013 Jun;3(6):690-703. doi: 10.1158/2159-8290.CD-12-0541. Epub 2013 Apr 1.

Abstract

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Down-Regulation
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins p21(ras)
  • Signal Transduction
  • Transcription Factors
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • KRAS protein, human
  • NF-kappa B
  • Proto-Oncogene Proteins
  • TAB1 protein, MAPKKK activator, vertebrate
  • Transcription Factors
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins