Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity.
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 conditions. 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 Q(o) site of mitochondrial complex III. Furthermore, disruption of mitochondrial function by loss 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.
Weinberg
Frank
F
Division of Pulmonary and Critical Care, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School Chicago, IL 60611, USA.
Hamanaka
Robert
R
Wheaton
William W
WW
Weinberg
Samuel
S
Joseph
Joy
J
Lopez
Marcos
M
Kalyanaraman
Balaraman
B
Mutlu
Gökhan M
GM
Budinger
G R Scott
GR
Chandel
Navdeep S
NS
D000332:Aerobiosis; D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D014450:Electron Transport Complex III / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010427:Pentose Phosphate Pathway; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D017382:Reactive Oxygen Species; D005973:Glutamine; D048049:Extracellular Signal-Regulated MAP Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D014450:Electron Transport Complex III