Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity

Frank Weinberg, Robert Hamanaka, William W. Wheaton, Samuel Weinberg, Joy Joseph, Marcos Lopez, Balaraman Kalyanaraman, Gökhan M. Mutlu, G. R.Scott Budinger, Navdeep S. Chandel

Research output: Contribution to journalArticlepeer-review

904 Scopus citations

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 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 Qo 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.

Original languageEnglish (US)
Pages (from-to)8788-8793
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number19
DOIs
StatePublished - May 11 2010

Keywords

  • Complex III
  • Glutamine
  • Glycolysis
  • Lung cancer
  • Warburg effect

ASJC Scopus subject areas

  • General

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