title: K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis.
abstract: Increased aerobic glycolysis and oxidative stress are important features of cancer cell metabolism, but the underlying biochemical and molecular mechanisms remain elusive. Using a tetracycline inducible model, we show that activation of K-ras(G12V) causes mitochondrial dysfunction, leading to decreased respiration, elevated glycolysis, and increased generation of reactive oxygen species. The K-RAS protein is associated with mitochondria, and induces a rapid suppression of respiratory chain complex-I and a decrease in mitochondrial transmembrane potential by affecting the cyclosporin-sensitive permeability transition pore. Furthermore, pre-induction of K-ras(G12V) expression in vitro to allow metabolic adaptation to high glycolytic metabolism enhances the ability of the transformed cells to form tumor in vivo. Our study suggests that induction of mitochondrial dysfunction is an important mechanism by which K-ras(G12V) causes metabolic changes and ROS stress in cancer cells, and promotes tumor development.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510275, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Hu
authors.forename: Weiqin
authors.initials: W
authors.lastname: Lu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Marcia
authors.initials: M
authors.lastname: Ogasawara
authors.forename: Dunyaporn
authors.initials: D
authors.lastname: Trachootham
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.forename: Helene
authors.initials: H
authors.lastname: Pelicano
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000818:Animals; D002460:Cell Line; D003524:Cyclosporins / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D003524:Cyclosporins; D017382:Reactive Oxygen Species; D018631:ras Proteins; D042967:Electron Transport Complex I; D004318:Doxycycline