title: Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect.
abstract: BACKGROUND
  The unique metabolism of tumors was described many years ago by Otto Warburg, who identified tumor cells with increased glycolysis and decreased mitochondrial activity. However, "aerobic glycolysis" generates fewer ATP per glucose molecule than mitochondrial oxidative phosphorylation, so in terms of energy production, it is unclear how increasing a less efficient process provides tumors with a growth advantage.
  
  
  RESULTS
  We carried out a screen for loss of genetic elements in pancreatic tumor cells that accelerated their growth as tumors, and identified mitochondrial ribosomal protein L28 (MRPL28). Knockdown of MRPL28 in these cells decreased mitochondrial activity, and increased glycolysis, but paradoxically, decreased cellular growth in vitro. Following Warburg's observations, this mutation causes decreased mitochondrial function, compensatory increase in glycolysis and accelerated growth in vivo. Likewise, knockdown of either mitochondrial ribosomal protein L12 (MRPL12) or cytochrome oxidase had a similar effect. Conversely, expression of the mitochondrial uncoupling protein 1 (UCP1) increased oxygen consumption and decreased tumor growth. Finally, treatment of tumor bearing animals with dichloroacetate (DCA) increased pyruvate consumption in the mitochondria, increased total oxygen consumption, increased tumor hypoxia and slowed tumor growth.
  
  
  CONCLUSIONS
  We interpret these findings to show that non-oncogenic genetic changes that alter mitochondrial metabolism can regulate tumor growth through modulation of the consumption of oxygen, which appears to be a rate limiting substrate for tumor proliferation.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Chen
authors.forename: Rob
authors.initials: R
authors.lastname: Cairns
authors.forename: Ioanna
authors.initials: I
authors.lastname: Papandreou
authors.forename: Albert
authors.initials: A
authors.lastname: Koong
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Denko
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D007473:Ion Channels / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000737:chemistry; D010101:Oxygen Consumption; D010190:Pancreatic Neoplasms / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C489320:RPL28 protein, human; D012269:Ribosomal Proteins; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1; D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid; D010100:Oxygen