HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations
Gregg L. Semenza
Gregg L. Semenza
Published September 3, 2013
Citation Information: J Clin Invest. 2013;123(9):3664-3671. https://doi.org/10.1172/JCI67230.
View: Text | PDF
Review Series

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

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.

Authors

Gregg L. Semenza

×

Figure 1

HIF-1 regulates the balance between O2 supply and demand.

Options: View larger image (or click on image) Download as PowerPoint
HIF-1 regulates the balance between O2 supply and demand. In well-oxyg...
In well-oxygenated cells, prolyl hydroxylase domain (PHD) proteins use O2 and α-ketoglutarate (αKG) to hydroxylate HIF-1α, which is then bound by VHL, ubiquitylated, and degraded by the proteasome. Under hypoxic conditions, the hydroxylation reaction is inhibited and HIF-1α accumulates and regulates cell proliferation directly or dimerizes with HIF-1β to activate the transcription of hundreds of target genes, many of which encode enzymes and transporters that control cell metabolism. Red and blue arrows indicate reactions that are favored in aerobic and hypoxic conditions, respectively.