HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations

J Clin Invest. 2013 Sep;123(9):3664-71. doi: 10.1172/JCI67230. Epub 2013 Sep 3.


Hypoxia occurs frequently in human cancers and induces adaptive changes in cell metabolism that include a switch from oxidative phosphorylation to glycolysis, increased glycogen synthesis, and a switch from glucose to glutamine as the major substrate for fatty acid synthesis. This broad metabolic reprogramming is coordinated at the transcriptional level by HIF-1, which functions as a master regulator to balance oxygen supply and demand. HIF-1 is also activated in cancer cells by tumor suppressor (e.g., VHL) loss of function and oncogene gain of function (leading to PI3K/AKT/mTOR activity) and mediates metabolic alterations that drive cancer progression and resistance to therapy. Inhibitors of HIF-1 or metabolic enzymes may impair the metabolic flexibility of cancer cells and make them more sensitive to anticancer drugs.

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.
  • Review

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Cell Hypoxia
  • Drug Resistance, Neoplasm
  • Energy Metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Oncogenes


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit