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Science 334 (6060): 1278-1283

Copyright © 2011 by the American Association for the Advancement of Science

Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses

Dimitrios Anastasiou,1,2 George Poulogiannis,1,2 John M. Asara,1,3 Matthew B. Boxer,4 Jian-kang Jiang,4 Min Shen,4 Gary Bellinger,1,5 Atsuo T. Sasaki,1,2 Jason W. Locasale,1,2 Douglas S. Auld,4,* Craig J. Thomas,4 Matthew G. Vander Heiden,5,6 Lewis C. Cantley1,2,{dagger}

Abstract: Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. We show that, in human lung cancer cells, acute increases in intracellular concentrations of ROS caused inhibition of the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation of Cys358. This inhibition of PKM2 is required to divert glucose flux into the pentose phosphate pathway and thereby generate sufficient reducing potential for detoxification of ROS. Lung cancer cells in which endogenous PKM2 was replaced with the Cys358 to Ser358 oxidation-resistant mutant exhibited increased sensitivity to oxidative stress and impaired tumor formation in a xenograft model. Besides promoting metabolic changes required for proliferation, the regulatory properties of PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress.

1 Beth Israel Deaconess Medical Center, Department of Medicine-Division of Signal Transduction, Boston, MA 02115, USA.
2 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
3 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
4 NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
5 Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
6 Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

* Present address: Novartis Institutes for Biomedical Research, Center for Proteomic Chemistry, Cambridge, MA 02139, USA.

{dagger} To whom correspondence should be addressed. E-mail: lewis_cantley{at}hms.harvard.edu


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