title: Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells.
abstract: Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells.
  
  
  
  We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention.
  
  
  
  We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma.
  
  
  
  Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice.
authors.affiliation: M.Sc. Programme in Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); B.Sc. Programme in Physiology, Newcastle University, Newcastle upon Tyne, UK (S.P.); Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK (I.W., R.M.); Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK (D.M.T., E.A.S.); Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Wellcome Trust Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK (A.R.J.).
authors.forename: Hua
authors.initials: H
authors.lastname: Lin
authors.affiliation: M.Sc. Programme in Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); B.Sc. Programme in Physiology, Newcastle University, Newcastle upon Tyne, UK (S.P.); Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK (I.W., R.M.); Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK (D.M.T., E.A.S.); Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Wellcome Trust Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK (A.R.J.).
authors.forename: Shaan
authors.initials: S
authors.lastname: Patel
authors.affiliation: M.Sc. Programme in Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); B.Sc. Programme in Physiology, Newcastle University, Newcastle upon Tyne, UK (S.P.); Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK (I.W., R.M.); Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK (D.M.T., E.A.S.); Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Wellcome Trust Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK (A.R.J.).
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Affleck
authors.affiliation: M.Sc. Programme in Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); B.Sc. Programme in Physiology, Newcastle University, Newcastle upon Tyne, UK (S.P.); Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK (I.W., R.M.); Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK (D.M.T., E.A.S.); Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Wellcome Trust Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK (A.R.J.).
authors.forename: Ian
authors.initials: I
authors.lastname: Wilson
authors.affiliation: M.Sc. Programme in Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); B.Sc. Programme in Physiology, Newcastle University, Newcastle upon Tyne, UK (S.P.); Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK (I.W., R.M.); Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK (D.M.T., E.A.S.); Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Wellcome Trust Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK (A.R.J.).
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.affiliation: M.Sc. Programme in Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); B.Sc. Programme in Physiology, Newcastle University, Newcastle upon Tyne, UK (S.P.); Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK (I.W., R.M.); Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK (D.M.T., E.A.S.); Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Wellcome Trust Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK (A.R.J.).
authors.forename: Abhijit R
authors.initials: AR
authors.lastname: Joshi
authors.affiliation: M.Sc. Programme in Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); B.Sc. Programme in Physiology, Newcastle University, Newcastle upon Tyne, UK (S.P.); Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK (I.W., R.M.); Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK (D.M.T., E.A.S.); Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Wellcome Trust Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK (A.R.J.).
authors.forename: Ross
authors.initials: R
authors.lastname: Maxwell
authors.affiliation: M.Sc. Programme in Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK (H.L., V.S.A.); B.Sc. Programme in Physiology, Newcastle University, Newcastle upon Tyne, UK (S.P.); Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK (I.W., R.M.); Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK (D.M.T., E.A.S.); Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Wellcome Trust Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK (D.M.T.); Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK (A.R.J.) elizabeth.stoll@ncl.ac.uk.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Stoll
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D004852:Epoxy Compounds; D005227:Fatty Acids; D007004:Hypoglycemic Agents; C054207:etomoxir
keywords: etomoxir; fatty acid oxidation; glioblastoma; glioma; metabolism