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PNAS 107 (19): 8788-8793

Copyright © 2010 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

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

Frank Weinberga, Robert Hamanakaa, William W. Wheatona, Samuel Weinberga, Joy Josephb, Marcos Lopezb, Balaraman Kalyanaramanb, Gökhan M. Mutlua, G. R. Scott Budingera, and Navdeep S. Chandela,c,d,1

aDivision of Pulmonary and Critical Care, Department of Medicine, cRobert H. Lurie Comprehensive Cancer Center, and dDepartment of Cell and Molecular Biology, Northwestern University Medical School Chicago, IL 60611; and bDepartment of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226

Edited by Lewis Clayton Cantley, Harvard Medical School, Boston, MA, and approved March 31, 2010 (received for review March 17, 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 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.

Key Words: Warburg Effect • glutamine • glycolysis • lung cancer • complex III


Freely available online through the PNAS open access option.

Author contributions: F.W., R.H., B.K., G.M.M., G.R.S.B., and N.S.C. designed research; F.W., R.H., W.W.W., S.W., and N.S.C. performed research; J.J., M.L., and B.K. contributed new reagents/analytic tools; F.W., R.H., G.M.M., G.R.S.B., and N.S.C. analyzed data; and F.W., R.H., G.R.S.B., and N.S.C. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1003428107/-/DCSupplemental.

1To whom correspondence should be addressed. Email: nav{at}northwestern.edu.


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