Novel role of NOX in supporting aerobic glycolysis in cancer cells with mitochondrial dysfunction and as a potential target for cancer therapy

• Published in: PLoS biology Vol. 10; no. 5; p. e1001326
• Main Authors: Lu, Weiqin, Hu, Yumin, Chen, Gang, Chen, Zhao, Zhang, Hui, Wang, Feng, Feng, Li, Pelicano, Helene, Wang, Hua, Keating, Michael J, Liu, Jinsong, McKeehan, Wallace, Wang, Huamin, Luo, Yongde, Huang, Peng
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2012; Public Library of Science (PLoS)
• Subjects: Animals; Biology; Cancer; Cancer therapies; Cell Survival; Defects; Deoxyribonucleic acid; DNA; Enzyme Activation; Experiments; Gene Knockdown Techniques; Genes, Neoplasm; Glycolysis; HEK293 Cells; Humans; Medicine; Mice; Mice, Nude; Mitochondria; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; NADPH Oxidase 1; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Oxidative Phosphorylation; Oxidative stress; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - pathology; Phosphorylation; Plasmids - genetics; Plasmids - metabolism; Proteins; Reactive Oxygen Species - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA, Small Interfering - therapeutic use; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Tetracycline - pharmacology; Transfection; Xenograft Model Antitumor Assays; Reactive Oxygen Species; Cell Survival; Genes, Neoplasm; Humans; Oxidative Phosphorylation; Gene Knockdown Techniques; Tetracycline; Xenograft Model Antitumor Assays; Mitochondria; Animals; Transfection; Mice, Nude; Plasmids; HEK293 Cells; Glycolysis; Mice; RNA, Small Interfering; Enzyme Activation; Pancreatic Neoplasms; NADPH Oxidase; Superoxide Dismutase
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1001326

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.