TNFalpha induces HIF-1alpha expression through activation of IKKbeta

Biochem Biophys Res Commun. 2009 Nov 27;389(4):640-4. doi: 10.1016/j.bbrc.2009.09.042. Epub 2009 Sep 17.

Abstract

The transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) is regulated by oxygen availability as well as various inflammatory mediators, including tumor necrosis factor alpha (TNFalpha). Early work suggested that the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are involved in TNFalpha-mediated HIF-1alpha accumulation and activation under normoxic conditions. Here, we provide evidence showing that IkappaB kinase beta (IKKbeta) is required for HIF-1alpha regulation by TNFalpha. We found that TNFalpha enhances HIF-1alpha protein expression in various breast cancer cell lines under either normoxic or hypoxia-mimicking conditions, but has little effect on the HIF-1alpha mRNA level. Increased HIF-1alpha expression was found in IKKbeta stable clones and transient transfectants, and depletion of IKKbeta consistently reduced the amount of HIF-1alpha protein. Treatment of cells with the IKKbeta inhibitor Bay 11-7082 reduced the TNFalpha-induced HIF-1alpha expression, suggesting that IKKbeta is required in this signaling pathway. Decreased expression of vascular endothelial growth factor (VEGF), a direct target of HIF-1alpha, was shown in IKKbeta-knockout mouse embryonic fibroblast cells. We further demonstrated a positive correlation between IKKbeta and VEGF expression in primary human breast cancer specimens. Our findings indicate that TNFalpha-induced HIF-1alpha accumulation is IKKbeta dependent, and may enable further understanding of the HIF-1alpha regulation by inflammatory signals.

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
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Gene Expression Regulation*
  • Gene Knockout Techniques
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • I-kappa B Kinase / antagonists & inhibitors
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Mice
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Endothelial Growth Factor A / biosynthesis

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Tumor Necrosis Factor-alpha
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • I-kappa B Kinase