Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

摘要: High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression poor clinical outcome. However, mechanistic relationship between metabolism malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to human head neck squamous cell carcinoma. PDC occurs via enhanced expression kinase-1 (PDK-1), which results inhibitory phosphorylation α (PDHα) subunit. We also demonstrate is associated normoxic stabilization malignancy-promoting transcription factor hypoxia-inducible factor-1α (HIF-1α) by glycolytic metabolites. Knockdown PDK-1 short hairpin RNA lowers PDHα phosphorylation, restores activity, reverts phenotype, decreases HIF-1α expression, hypoxic survival, invasiveness, inhibits tumor growth. an HIF-1-regulated gene, these data suggest buildup metabolites, resulting from high may turn promote HIF-1 activation, thus sustaining a feed-forward loop for progression. In addition providing anabolic support cells, fuel supports phenotype. Correction abnormalities offers unique opportunities treatment potentially synergize other therapies.