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-rasG12V 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-rasG12V 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-rasG12V causes metabolic changes and ROS stress in cancer cells, and promotes tumor development.
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Acknowledgements
We thank Kenneth Dunner for expert technical assistance in electron microscopic analysis. This work was supported in part by grants CA085563, CA100428 and CA109041 from the National Institutes of Health.
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
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Supplementary information, Figure S1
Morphological alteration of T-Rex cells after K-ras induction. (PDF 170 kb)
Supplementary information, Figure S2
Effect of K-rasG12V induction on the expression of SOD2 mRNA in HEK293 cells. (PDF 9 kb)
Supplementary information, Figure S3
Comparison of trypsin digestion of K-RAS protein in isolated mitochondria and free K-RAS in protein extracts. (PDF 21 kb)
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Hu, Y., Lu, W., Chen, G. et al. K-rasG12V transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res 22, 399–412 (2012). https://doi.org/10.1038/cr.2011.145
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DOI: https://doi.org/10.1038/cr.2011.145
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