PPAR gamma Coactivator-1 alpha Suppresses Metastasis of Hepatocellular Carcinoma by Inhibiting Warburg Effect by PPAR gamma-Dependent WNT/beta-Catenin/Pyruvate Dehydrogenase Kinase Isozyme 1 Axis

Abstract

Background and Aims Peroxisome proliferator-activated receptor-gamma (PPAR gamma) coactivator-1 alpha (PGC1 alpha) is a key regulator of mitochondrial biogenesis and respiration. PGC1 alpha is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in the progression of hepatocellular carcinoma (HCC) remains unclear. Approach and Results In this study, we observed that PGC1 alpha was down-regulated in human HCC. A clinical study showed that low levels of PGC1 alpha expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1 alpha inhibited the migration and invasion of HCC cells with both in vitro experiments and in vivo mouse models. Mechanistically, PGC1 alpha suppressed the Warburg effect through down-regulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by the WNT/beta-catenin pathway, and inhibition of the WNT/beta-catenin pathway was induced by activation of PPAR gamma. Conclusions Low levels of PGC1 alpha expression indicate a poor prognosis for HCC patients. PGC1 alpha suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating the WNT/beta-catenin/PDK1 axis, which depends on PPAR gamma. PGC1 alpha is a potential factor for predicting prognosis and a therapeutic target for HCC patients.