Volume 22, No 2, Feb 2012

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 22 Issue 2, February 2012: 399-412

ORIGINAL ARTICLES

K-ras^G12V transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis

Yumin Hu^1,2,*, Weiqin Lu^2,*, Gang Chen^2,*, Peng Wang¹, Zhao Chen2, Yan Zhou², Marcia Ogasawara², Dunyaporn Trachootham^2,3, Li Feng², Helene Pelicano²,

¹State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou 510275, China

²Department of Molecular Pathology, Unit 951, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
³Faculty of Dentistry, Thammasat University, Pathum-thani 12121, Thailand
⁴Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
⁵Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Correspondence: Peng Huang,(phuang@mdanderson.org)

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.

Cell Research (2012) 22:399-412. doi:10.1038/cr.2011.145; published online 30 August 2011

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