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

Science, 2 December 2011
Vol. 334, Issue 6060, p. 1278-1283
DOI: 10.1126/science.1211485

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

  1. Dimitrios Anastasiou1,2,
  2. George Poulogiannis1,2,
  3. John M. Asara1,3,
  4. Matthew B. Boxer4,
  5. Jian-kang Jiang4,
  6. Min Shen4,
  7. Gary Bellinger1,5,
  8. Atsuo T. Sasaki1,2,
  9. Jason W. Locasale1,2,
  10. Douglas S. Auld4,*,
  11. Craig J. Thomas4,
  12. Matthew G. Vander Heiden5,6,
  13. Lewis C. Cantley1,2,
  1. 1Beth Israel Deaconess Medical Center, Department of Medicine-Division of Signal Transduction, Boston, MA 02115, USA.
  2. 2Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  3. 3Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  4. 4NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
  5. 5Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  6. 6Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  1. To whom correspondence should be addressed. E-mail: lewis_cantley{at}


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.

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

  • Received for publication 20 July 2011.
  • Accepted for publication 21 October 2011.


D. Anastasiou, G. Poulogiannis, J. M. Asara, M. B. Boxer, J.-k. Jiang, M. Shen, G. Bellinger, A. T. Sasaki, J. W. Locasale, D. S. Auld, C. J. Thomas, M. G. Vander Heiden, and L. C. Cantley, Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses. Science 334, 1278-1283 (2011).

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