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Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
- Source :
- Proceedings of the National Academy of Sciences of the United States. May 11, 2010, Vol. 107 Issue 19, p8788, 6 p.
- Publication Year :
- 2010
-
Abstract
- Otto Warburg's theory on the origins of cancer postulates that tumor cells have defects in mitochondrial oxidative phosphorylation and therefore rely on high levels of aerobic glycolysis as the major source of ATP to fuel cellular proliferation (the Warburg effect). This is in contrast to normal cells, which primarily utilize oxidative phosphorylation for growth and survival. Here we report that the major function of glucose metabolism for Kras-induced anchorage-independent growth, a hallmark of transformed cells, is to support the pentose phosphate pathway. The major function of glycolytic ATP is to support growth under hypoxic conclitions. Glutamine conversion into the tricarboxylic acid cycle intermediate alpha-ketoglutarate through glutaminase and alanine aminotransferase is essential for Kras-induced anchorage-independent growth. Mitochondrial metabolism allows for the generation of reactive oxygen species (ROS) which are required for Kras-induced anchorage-independent growth through regulation of the ERK MAPK signaling pathway. We show that the major source of ROS generation required for anchorage-independent growth is the Qo site of mitochondrial complex III. Furthermore, disruption of mitochondrial function by Ioss of the mitochondrial transcription factor A (TFAM) gene reduced tumorigenesis in an oncogenic Kras-driven mouse model of lung cancer. These results demonstrate that mitochondrial metabolism and mitochondrial ROS generation are essential for Kras-induced cell proliferation and tumorigenesis. Warburg Effect | glutamine | glycolysis | lung cancer | complex III doi/10.1073/pnas.1003428107
- Subjects :
- Carcinogenesis -- Physiological aspects
Carcinogenesis -- Genetic aspects
Carcinogenesis -- Research
Cell metabolism -- Physiological aspects
Cell metabolism -- Genetic aspects
Mitochondria -- Physiological aspects
Mitochondria -- Genetic aspects
Reactive oxygen species -- Physiological aspects
Reactive oxygen species -- Research
Science and technology
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 107
- Issue :
- 19
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.227362805