Active glycolytic metabolism in CD133(+) hepatocellular cancer stem cells: regulation by MIR-122.
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.
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Kyoungsub
K
Song
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Hyunjoo
H
Kwon
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Chang
C
Han
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Jinqiang
J
Zhang
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Srikanta
S
Dash
Department of Biochemistry, College of Medicine, Cancer Research Institute and Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea.
Kyu
K
Lim
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Tong
T
Wu
D000071916:AC133 Antigen; D000255:Adenosine Triphosphate / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D019344:Lactic Acid / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C000631432:PDK4 protein, human; C000606023:PROM1 protein, human; D010455:Peptides; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases
CD133; cancer stem cells; glycolysis; miR-122