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

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

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  • 1Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Abstract

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.

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