title: Nodal regulates energy metabolism in glioma cells by inducing expression of hypoxia-inducible factor 1α.
abstract: BACKGROUND
  A shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis is the biochemical hallmark of malignant cancer cells.
  
  
  METHODS
  In the present study, we demonstrated that Nodal stimulated the expression of glycolytic enzymes and decreased reliance on mitochondrial oxidative phosphorylation in human glioma cancer cells. The shift in glucose metabolism was mediated by induction of the hypoxia-inducible factor (HIF).
  
  
  RESULTS
  Nodal protein expression was shown to be correlated with expression levels of glucose transporter (Glut)-1, hexokinase (HK)-II, pyruvate dehydrogenase kinase (PDK)-1, the phosphorylation level of pyruvate dehydrogenase (PDH), glucose uptake, and lactate accumulation in human glioma cells. These effects were inversely correlated with mitochondrial oxygen consumption and ATP production. Knockdown of Nodal expression with specific small hairpin RNA reduced Glut-1, HK-II, and PDK-1 expressions and PDH phosphorylation. Nodal knockdown also reduced glucose uptake and lactate generation, which in turn increased mitochondrial membrane potential (Ψ), O2 utilization, and ATP synthesis. The ectopic expression of Nodal in low-expressing Nodal glioma cells resulted in the opposite results compared with those of Nodal knockdown glioma cells. Treatment of cells with recombinant Nodal increased HIF-1 expression, and this effect was regulated at the transcriptional level. Blockage of the Nodal receptor by a pharmacological inhibitor or Nodal knockdown in U87MG cells decreased HIF-1α expression. Furthermore, HIF-1α knockdown in U87MG cells decreased Glut-1, HK-II, and PDK-1 expressions and PDH phosphorylation, which were similar to results in Nodal knockdown cells.
  
  
  CONCLUSIONS
  Taken together, these results suggest that Nodal affects energy metabolism through HIF-1α.
authors.affiliation: Corresponding Authors: Horng-Mo Lee, PhD, Department of Medical Laboratory Sciences and Biotechnology, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. leehorng@tmu.edu.tw Hsin-I Ma, Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, No.325, Sec.2, Chenggong Rd., Neihu District, Taipei 114, Taiwan, ROC.
authors.forename: Jing-Huei
authors.initials: JH
authors.lastname: Lai
authors.forename: Hsun-Jin
authors.initials: HJ
authors.lastname: Jan
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Liu
authors.forename: Chin-Cheng
authors.initials: CC
authors.lastname: Lee
authors.forename: Shyang-Guang
authors.initials: SG
authors.lastname: Wang
authors.forename: Dueng-Yuan
authors.initials: DY
authors.lastname: Hueng
authors.forename: Yung-Yen
authors.initials: YY
authors.lastname: Cheng
authors.forename: Horng-Mo
authors.initials: HM
authors.lastname: Lee
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Ma
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D055457:Nodal Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C526007:NODAL protein, human; D055457:Nodal Protein; D034741:RNA, Small Interfering; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D008156:Luciferases; D005947:Glucose
keywords: Glut-1; HIF-1; Nodal; energy metabolism; gliomas
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