title: Novel role of NOX in supporting aerobic glycolysis in cancer cells with mitochondrial dysfunction and as a potential target for cancer therapy.
abstract: Elevated aerobic glycolysis in cancer cells (the Warburg effect) may be attributed to respiration injury or mitochondrial dysfunction, but the underlying mechanisms and therapeutic significance remain elusive. Here we report that induction of mitochondrial respiratory defect by tetracycline-controlled expression of a dominant negative form of DNA polymerase γ causes a metabolic shift from oxidative phosphorylation to glycolysis and increases ROS generation. We show that upregulation of NOX is critical to support the elevated glycolysis by providing additional NAD+. The upregulation of NOX is also consistently observed in cancer cells with compromised mitochondria due to the activation of oncogenic Ras or loss of p53, and in primary pancreatic cancer tissues. Suppression of NOX by chemical inhibition or genetic knockdown of gene expression selectively impacts cancer cells with mitochondrial dysfunction, leading to a decrease in cellular glycolysis, a loss of cell viability, and inhibition of cancer growth in vivo. Our study reveals a previously unrecognized function of NOX in cancer metabolism and suggests that NOX is a potential novel target for cancer treatment.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Lu
authors.forename: Yumin
authors.initials: Y
authors.lastname: Hu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.forename: Helene
authors.initials: H
authors.lastname: Pelicano
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Wallace
authors.initials: W
authors.lastname: McKeehan
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Yongde
authors.initials: Y
authors.lastname: Luo
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000818:Animals; D002470:Cell Survival; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D052138:Genes, Neoplasm; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C086986:CYBA protein, human; D013752:Tetracycline