The Warburg effect in cancer cells refers to preferential aerobic glycolysis over oxidative phosphorylation even in the presence of adequate oxygen. The oncometabolite that most directly promotes HIF-1alpha stabilization in the normoxic tumor microenvironment of IDH1-mutant gliomas is:
- A Succinate, which inhibits prolyl hydroxylase domain (PHD) enzymes
- B Fumarate, which alkylates and inhibits PHD2 via succination
- C 2-hydroxyglutarate (2-HG), which competitively inhibits alpha-ketoglutarate-dependent dioxygenases including PHDs ✓
- D Lactate, which acidifies the cytosol and prevents VHL-mediated HIF-1alpha ubiquitination
Explanation
IDH1/2 mutations produce the oncometabolite R-2-hydroxyglutarate (2-HG) from alpha-ketoglutarate. 2-HG competitively inhibits alpha-KG-dependent dioxygenases, including TET2, histone demethylases, and prolyl hydroxylase domain (PHD) enzymes. PHD inhibition prevents hydroxylation of HIF-1alpha, which is required for VHL-mediated proteasomal degradation, leading to normoxic HIF-1alpha stabilization and a pseudo-hypoxic transcriptional program. Succinate accumulation (SDH mutations) and fumarate (FH mutations) similarly inhibit PHDs, but these are not the mechanism in IDH-mutant tumors. Lactate acidification is not the primary mechanism for HIF stabilization.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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