Error message

No crossref credentials set for sci

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}hms.harvard.edu

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.

  • * 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.

Citation:

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).

Pyruvate kinase M2 at a glance
W. Yang, and Z. Lu
J. Cell Sci. 128, 1655-1660 (1 May 2015)

Signal Transduction in Cancer
R. Sever, and J. S. Brugge
Cold Spring Harb Perspect Med 5, a006098-a006098 (1 April 2015)

Stem cells and the impact of ROS signaling
C. L. Bigarella, R. Liang, and S. Ghaffari
Development 141, 4206-4218 (15 November 2014)

Oncogenic Properties of a Spermatogenic Meiotic Variant of Fer Kinase Expressed in Somatic Cells
E. Yaffe, E. Hikri, Y. Elkis, O. Cohen, A. Segal, A. Makovski, A. Varvak, S. Shpungin, and U. Nir
Cancer Res. 74, 6474-6485 (15 November 2014)

Angiogenesis revisited - role and therapeutic potential of targeting endothelial metabolism
P. Stapor, X. Wang, J. Goveia, S. Moens, and P. Carmeliet
J. Cell Sci. 127, 4331-4341 (15 October 2014)

Tadpole tail regeneration in Xenopus
Y. Chen, N. R. Love, and E. Amaya
Biochm. Soc. Trans. 42, 617-623 (1 June 2014)

Missense Mutations in Pyruvate Kinase M2 Promote Cancer Metabolism, Oxidative Endurance, Anchorage Independence, and Tumor Growth in a Dominant Negative Manner
M. A. Iqbal, F. A. Siddiqui, N. Chaman, V. Gupta, B. Kumar, P. Gopinath, and R. N. K. Bamezai
J Biol Chem 289, 8098-8105 (21 March 2014)

Inhibition of triosephosphate isomerase by phosphoenolpyruvate in the feedback-regulation of glycolysis
N.-M. Gruning, D. Du, M. A. Keller, B. F. Luisi, and M. Ralser
Open Biol 4, 130232-130232 (1 March 2014)

Ethanol-Induced Upregulation of 10-Formyltetrahydrofolate Dehydrogenase Helps Relieve Ethanol-Induced Oxidative Stress
T.-H. Hsiao, C.-J. Lin, Y.-S. Chung, G.-H. Lee, T.-T. Kao, W.-N. Chang, B.-H. Chen, J.-J. Hung, and T.-F. Fu
Mol. Cell. Biol. 34, 498-509 (1 February 2014)

JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1{alpha}-mediated glucose metabolism
H.-J. Wang, Y.-J. Hsieh, W.-C. Cheng, C.-P. Lin, Y.-s. Lin, S.-F. Yang, C.-C. Chen, Y. Izumiya, J.-S. Yu, H.-J. Kung et al.
Proc. Natl. Acad. Sci. USA 111, 279-284 (7 January 2014)

Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step
A. A. Shestov, X. Liu, Z. Ser, A. A. Cluntun, Y. P. Hung, L. Huang, D. Kim, A. Le, G. Yellen, J. G. Albeck et al.
elife 3, e03342-e03342 (1 January 2014)

Direct Measurements of Oscillatory Glycolysis in Pancreatic Islet {beta}-Cells Using Novel Fluorescence Resonance Energy Transfer (FRET) Biosensors for Pyruvate Kinase M2 Activity
M. J. Merrins, A. R. Van Dyke, A. K. Mapp, M. A. Rizzo, and L. S. Satin
J Biol Chem 288, 33312-33322 (15 November 2013)

Selective Targeting of the Cysteine Proteome by Thioredoxin and Glutathione Redox Systems
Y.-M. Go, J. R. Roede, D. I. Walker, D. M. Duong, N. T. Seyfried, M. Orr, Y. Liang, K. D. Pennell, and D. P. Jones
MCP 12, 3285-3296 (1 November 2013)

FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells
H. Yeo, C. A. Lyssiotis, Y. Zhang, H. Ying, J. M. Asara, L. C. Cantley, and J.-H. Paik
EMBO J. 32, 2589-2602 (2 October 2013)

Pharmacologic Activation of PKM2 Slows Lung Tumor Xenograft Growth
K. M. Parnell, J. M. Foulks, R. N. Nix, A. Clifford, J. Bullough, B. Luo, A. Senina, D. Vollmer, J. Liu, V. McCarthy et al.
Molecular Cancer Therapeutics 12, 1453-1460 (1 August 2013)

A Metabolomics-driven Elucidation of the Anti-obesity Mechanisms of Xanthohumol
J. S. Kirkwood, L. L. Legette, C. L. Miranda, Y. Jiang, and J. F. Stevens
J Biol Chem 288, 19000-19013 (28 June 2013)

Antioxidant Enzymes Mediate Survival of Breast Cancer Cells Deprived of Extracellular Matrix
C. A. Davison, S. M. Durbin, M. R. Thau, V. R. Zellmer, S. E. Chapman, J. Diener, C. Wathen, W. M. Leevy, and Z. T. Schafer
Cancer Res. 73, 3704-3715 (15 June 2013)

Protein Tyrosine Phosphatase 1B Regulates Pyruvate Kinase M2 Tyrosine Phosphorylation
A. Bettaieb, J. Bakke, N. Nagata, K. Matsuo, Y. Xi, S. Liu, D. AbouBechara, R. Melhem, K. Stanhope, B. Cummings et al.
J Biol Chem 288, 17360-17371 (14 June 2013)

M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation
H. P. Morgan, F. J. O'Reilly, M. A. Wear, J. R. O'Neill, L. A. Fothergill-Gilmore, T. Hupp, and M. D. Walkinshaw
Proc. Natl. Acad. Sci. USA 110, 5881-5886 (9 April 2013)

Allosteric Regulation of PKM2 Allows Cellular Adaptation to Different Physiological States
D. Y. Gui, C. A. Lewis, and M. G. Vander Heiden
Sci Signal 6, pe7-pe7 (19 February 2013)

Metabolic changes in cancer: beyond the Warburg effect
W. Wu, and S. Zhao
Acta Biochim Biophys Sin 45, 18-26 (1 January 2013)

The Metabolomic Signature of Malignant Glioma Reflects Accelerated Anabolic Metabolism
P. Chinnaiyan, E. Kensicki, G. Bloom, A. Prabhu, B. Sarcar, S. Kahali, S. Eschrich, X. Qu, P. Forsyth, R. Gillies et al.
Cancer Res. 72, 5878-5888 (15 November 2012)

Cancer Metabolism: What we Can Learn from Proteomic Analysis by Mass Spectrometry
W. Zhou, L. A. Liotta, and E. F. Petricoin
Cancer Genomics Proteomics 9, 373-381 (1 November 2012)

Molecular Pathways: Tumor Cells Co-opt the Brain-Specific Metabolism Gene CPT1C to Promote Survival
P. T. Reilly, and T. W. Mak
Clin. Cancer Res. 18, 5850-5855 (1 November 2012)

Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides
Z. Wang, H. Y. Jeon, F. Rigo, C. F. Bennett, and A. R. Krainer
Open Biol 2, 120133-120133 (31 October 2012)

Targeting Cancer Metabolism
B. A. Teicher, W. M. Linehan, and L. J. Helman
Clin. Cancer Res. 18, 5537-5545 (15 October 2012)

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells
M. Tamada, M. Suematsu, and H. Saya
Clin. Cancer Res. 18, 5554-5561 (15 October 2012)

Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay
T. Fiaschi, A. Marini, E. Giannoni, M. L. Taddei, P. Gandellini, A. De Donatis, M. Lanciotti, S. Serni, P. Cirri, P. Chiarugi et al.
Cancer Res. 72, 5130-5140 (1 October 2012)

Cancer Cell Metabolism: One Hallmark, Many Faces
J. R. Cantor, and D. M. Sabatini
Cancer Discovery 2, 881-898 (1 October 2012)

Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism
W. Yi, P. M. Clark, D. E. Mason, M. C. Keenan, C. Hill, W. A. Goddard, E. C. Peters, E. M. Driggers, and L. C. Hsieh-Wilson
Science 337, 975-980 (24 August 2012)

Signaling in Control of Cell Growth and Metabolism
P. S. Ward, and C. B. Thompson
Cold Spring Harb. Perspect. Biol. 4, a006783-a006783 (1 July 2012)

Combination of an Allosteric Akt Inhibitor MK-2206 with Etoposide or Rapamycin Enhances the Antitumor Growth Effect in Neuroblastoma
Z. Li, S. Yan, N. Attayan, S. Ramalingam, and C. J. Thiele
Clin. Cancer Res. 18, 3603-3615 (1 July 2012)

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT) Activity by Small Molecule GMX1778 Regulates Reactive Oxygen Species (ROS)-mediated Cytotoxicity in a p53- and Nicotinic Acid Phosphoribosyltransferase1 (NAPRT1)-dependent Manner
D. Cerna, H. Li, S. Flaherty, N. Takebe, C. N. Coleman, and S. S. Yoo
J Biol Chem 287, 22408-22417 (22 June 2012)

Links between metabolism and cancer
C. V. Dang, H. Li, S. Flaherty, N. Takebe, C. N. Coleman, and S. S. Yoo
Genes Dev. 26, 877-890 (1 May 2012)

Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival
S. Ros, C. R. Santos, S. Moco, F. Baenke, G. Kelly, M. Howell, N. Zamboni, and A. Schulze
Cancer Discovery 2, 328-343 (1 April 2012)

Regulation of intracellular signalling through cysteine oxidation by reactive oxygen species
H. Miki, and Y. Funato
J Biochem 151, 255-261 (1 March 2012)

Targeting glucose metabolism for cancer therapy
R. B. Hamanaka, and N. S. Chandel
JEM 209, 211-215 (13 February 2012)

Warburg Effect and Redox Balance
R. B. Hamanaka, and N. S. Chandel
Science 334, 1219-1220 (2 December 2011)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882