title: Tumor suppressor WWOX moderates the mitochondrial respiratory complex.
abstract: Fragile site FRA16D exhibits DNA instability in cancer, resulting in diminished levels of protein from the WWOX gene that spans it. WWOX suppresses tumor growth by an undefined mechanism. WWOX participates in pathways involving aerobic metabolism and reactive oxygen species. WWOX comprises two WW domains as well as a short-chain dehydrogenase/reductase enzyme. Herein is described an in vivo genetic analysis in Drosophila melanogaster to identify functional interactions between WWOX and metabolic pathways. Altered WWOX levels modulate variable cellular outgrowths caused by genetic deficiencies of components of the mitochondrial respiratory complexes. This modulation requires the enzyme active site of WWOX, and the defective respiratory complex-induced cellular outgrowths are mediated by reactive oxygen species, dependent upon the Akt pathway and sensitive to levels of autophagy and hypoxia-inducible factor. WWOX is known to contribute to homeostasis by regulating the balance between oxidative phosphorylation and glycolysis. Reduction of WWOX levels results in diminished ability to respond to metabolic perturbation of normal cell growth. Thus, the ability of WWOX to facilitate escape from mitochondrial damage-induced glycolysis (Warburg effect) is, therefore, a plausible mechanism for its tumor suppressor activity.
authors.affiliation: Department of Genetics and Evolution and Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Choo
authors.affiliation: Department of Genetics and Evolution and Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Louise V
authors.initials: LV
authors.lastname: O'Keefe
authors.affiliation: Department of Genetics and Evolution and Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Cheng Shoou
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Genetics and Evolution and Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Gregory
authors.affiliation: Department of Genetics and Evolution and Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Shaukat
authors.affiliation: Department of Genetics and Evolution and Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Colella
authors.affiliation: Department of Genetics and Evolution and Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Kristie
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Genetics and Evolution and Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Donna
authors.initials: D
authors.lastname: Denton
authors.affiliation: Department of Genetics and Evolution and Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Richards
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D049109:Cell Proliferation; D043283:Chromosome Fragile Sites; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics*; D006706:Homeostasis; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; C559480:WWOX protein, Drosophila; C036543:short chain trans-2-enoyl-CoA reductase; D009247:NADH, NADPH Oxidoreductases; D064429:Fatty Acid Synthases; D042967:Electron Transport Complex I