KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma

Cancer Cell. 2012 Jan 17;21(1):105-20. doi: 10.1016/j.ccr.2011.12.006.

Abstract

Constitutive Kras and NF-κB activation is identified as signature alterations in pancreatic ductal adenocarcinoma (PDAC). However, how NF-κB is activated in PDAC is not yet understood. Here, we report that pancreas-targeted IKK2/β inactivation inhibited NF-κB activation and PDAC development in Kras(G12D) and Kras(G12D);Ink4a/Arf(F/F) mice, demonstrating a mechanistic link between IKK2/β and Kras(G12D) in PDAC inception. Our findings reveal that Kras(G12D)-activated AP-1 induces IL-1α, which, in turn, activates NF-κB and its target genes IL-1α and p62, to initiate IL-1α/p62 feedforward loops for inducing and sustaining NF-κB activity. Furthermore, IL-1α overexpression correlates with Kras mutation, NF-κB activity, and poor survival in PDAC patients. Therefore, our findings demonstrate the mechanism by which IKK2/β/NF-κB is activated by Kras(G12D) through dual feedforward loops of IL-1α/p62.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines / antagonists & inhibitors
  • Cytokines / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • I-kappa B Kinase / metabolism*
  • Interleukin-1alpha / genetics
  • Interleukin-1alpha / metabolism*
  • Mice
  • Mutation
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Proto-Oncogene Proteins p21(ras) / physiology
  • Sequestosome-1 Protein
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism
  • ras Proteins / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Interleukin-1alpha
  • KRAS protein, human
  • NF-kappa B
  • Proto-Oncogene Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Transcription Factor AP-1
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins

Associated data

  • GEO/GSE33323