IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway

Cell. 2007 Aug 10;130(3):440-55. doi: 10.1016/j.cell.2007.05.058.

Abstract

TNFalpha has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKbeta, a major downstream kinase in the TNFalpha signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKbeta-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKbeta is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Humans
  • I-kappa B Kinase / physiology*
  • Inflammation Mediators / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Pathologic / enzymology*
  • Neovascularization, Pathologic / metabolism
  • Phosphorylation
  • Protein Kinases / physiology*
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Necrosis Factor-alpha / physiology
  • Tumor Suppressor Proteins / antagonists & inhibitors*
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology
  • Vascular Endothelial Growth Factor A / biosynthesis

Substances

  • Inflammation Mediators
  • TSC1 protein, human
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • I-kappa B Kinase