Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity

PLoS One. 2013;8(1):e53676. doi: 10.1371/journal.pone.0053676. Epub 2013 Jan 3.

Abstract

Background: Increased levels of NF-κB are hallmarks of pancreatic ductal adenocarcinoma (PDAC) and both classical and alternative NF-κB activation pathways have been implicated.

Methodology/principal findings: Here we show that activation of the alternative pathway is a source for the high basal NF-κB activity in PDAC cell lines. Increased activity of the p52/RelB NF-κB complex is mediated through stabilization and activation of NF-κB-inducing kinase (NIK). We identify proteasomal downregulation of TNF receptor-associated factor 2 (TRAF2) as a mechanism by which levels of active NIK are increased in PDAC cell lines. Such upregulation of NIK expression and activity levels relays to increased proliferation and anchorage-independent growth, but not migration or survival of PDAC cells.

Conclusions/significance: Rapid growth is one characteristic of pancreatic cancer. Our data indicates that the TRAF2/NIK/NF-κB2 pathway regulates PDAC cell tumorigenicity and could be a valuable target for therapy of this cancer.

Publication types

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

MeSH terms

  • Agar / chemistry
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Chemotaxis
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • NF-kappa B p52 Subunit / metabolism*
  • Pancreatic Neoplasms / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • TNF Receptor-Associated Factor 2 / metabolism*
  • Tetrazolium Salts / pharmacology
  • Thiazoles / pharmacology

Substances

  • NF-kappa B p52 Subunit
  • NFKB2 protein, human
  • TNF Receptor-Associated Factor 2
  • Tetrazolium Salts
  • Thiazoles
  • Agar
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase
  • Proteasome Endopeptidase Complex
  • thiazolyl blue