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.
Copyright © 2012 Elsevier Inc. All rights reserved.
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