Overexpression of Pyruvate Dehydrogenase E1α Subunit Inhibits Warburg Effect and Induces Cell Apoptosis Through Mitochondria-Mediated Pathway in Hepatocellular Carcinoma

Most cancers rely disproportionately on glycolysis for energy even in the presence of an adequate oxygen supply, a condition known as "aerobic glycolysis," or the "Warburg effect." Pyruvate dehydrogenase E1 alpha sub-unit (PDHA1) is one of the main factors for the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis and has been suggested to be closely associated with tumorigenesis. Here we observed that the PDHA1 protein was reduced in hepatocellular carcinoma (HCC) specimens by immunohistochemistry and Western blot, which was significantly associated with poor overall survival. To further analyze the function of PDHA 1 in cancer cells, PDHA I was upregulated in the HCC cell lines SMMC-7721 and HepG2. The results demonstrated that overexpression of the PDHA I gene inhibited aerobic glycolysis with lower lactate via increased PDH activity; meanwhile, nitochondrial OXPHOS was enhanced accompanied with higher ATP and lower glucose consumption. We also found that apoptosis was promoted and intrinsic pathway proteins were increased in PDHA 1-overexpressing cells. Collectively, our data indicate that reduced PDHA I protein expression is associated with the poor clinical outcome of HCC. Upregulated PDHA 1 gene expression can inhibit the Warburg effect and enhance the mitochondria-mediated apoptosis pathway.