Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 9, Pages 3664-3671Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI67230
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Funding
- C. Michael Armstrong Professorship at Johns Hopkins University School of Medicine
- Johns Hopkins Institute for Cell Engineering
- American Cancer Society
- Department of Defense [W81XWH-12-1-0464]
- NIH [U54-CA143868, HHS-N268201000032C]
- Susan G. Komen for the Cure Research Programs
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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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