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

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.