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.
Keywords:
CD133; cancer stem cells; glycolysis; miR-122.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AC133 Antigen
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Adenosine Triphosphate / metabolism
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Antigens, CD / metabolism*
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Blotting, Western
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology*
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Cell Proliferation
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Gene Expression Regulation, Neoplastic
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Glycolysis / physiology*
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Glycoproteins / metabolism*
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Humans
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Immunoenzyme Techniques
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Lactic Acid / metabolism
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology*
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MicroRNAs / genetics*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Peptides / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Spheroids, Cellular / metabolism
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Spheroids, Cellular / pathology
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Tumor Cells, Cultured
Substances
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AC133 Antigen
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Antigens, CD
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Glycoproteins
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MIRN122 microRNA, human
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MicroRNAs
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PDK4 protein, human
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PROM1 protein, human
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Peptides
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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RNA, Messenger
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Lactic Acid
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Adenosine Triphosphate
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Protein Serine-Threonine Kinases