Active glycolytic metabolism in CD133(+) hepatocellular cancer stem cells: regulation by MIR-122

Abstract

// Kyoungsub Song 1 , Hyunjoo Kwon 1 , Chang Han 1 , Jinqiang Zhang 1 , Srikanta Dash 1 , Kyu Lim 2 , Tong Wu 1 1 Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA 2 Department of Biochemistry, College of Medicine, Cancer Research Institute and Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea Correspondence to: Tong Wu, e-mail: twu@tulane.edu Keywords: CD133, cancer stem cells, glycolysis, miR-122 Received: March 13, 2015      Accepted: September 23, 2015      Published: October 19, 2015 ABSTRACT Although altered metabolic pathway is an important diagnostic maker and therapeutic target in cancer, it is poorly understood in cancer stem cells (CSCs). Here we show that the CD133 (+) hepatocellular CSCs have distinct metabolic properties, characterized by more active glycolysis over oxidative phosphorylation, compared to the CD133 (−) cells. Inhibition of PDK4 and LDHA markedly suppresses CD133 (+) stemness characteristics and overcome resistance to sorafenib (current chemotherapeutic agent for hepatocellular cancer). Addition of glucose or lactate to CD133 (−) cells promotes CSC phenotypes, as evidenced by increased CD133 (+) cell population, elevated stemness gene expression and enhanced spheroid formation. Furthermore, the liver-specific miRNA, miR-122, inhibits CSC phenotypes by regulating glycolysis through targeting PDK4. Our findings suggest that enhanced glycolysis is associated with CD133 (+) stem-like characteristics and that metabolic reprogramming through miR-122 or PDK4 may represent a novel therapeutic approach for the treatment of hepatocellular cancer.