Nothing Special   »   [go: up one dir, main page]
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

Nature volume 452, pages 230–233 (2008)Cite this article

Abstract

Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago1. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase2. Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Tumour tissues and cell lines express the M2 isoform of pyruvate kinase.
Figure 2: PKM2 knockdown is rescued by expression of PKM1 in vitro.
Figure 3: M1 expression results in increased oxidative phosphorylation.
Figure 4: M1 expression reduces the tumorigenicity of lung cancer cells.

Similar content being viewed by others

References

  1. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956)

    Article  CAS  ADS  Google Scholar 

  2. Mazurek, S., Boschek, C. B., Hugo, F. & Eigenbrodt, E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin. Cancer Biol. 15, 300–308 (2005)

    Article  CAS  Google Scholar 

  3. Fantin, V. R., St-Pierre, J. & Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434 (2006)

    Article  CAS  Google Scholar 

  4. Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Med. 10, 594–601 (2004)

    Article  CAS  Google Scholar 

  5. Altenberg, B. & Greulich, K. O. Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 84, 1014–1020 (2004)

    Article  CAS  Google Scholar 

  6. Jurica, M. S. et al. The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate. Structure 6, 195–210 (1998)

    Article  CAS  Google Scholar 

  7. Dombrauckas, J. D., Santarsiero, B. D. & Mesecar, A. D. Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry 44, 9417–9429 (2005)

    Article  CAS  Google Scholar 

  8. Muller, W. J., Sinn, E., Pattengale, P. K., Wallace, R. & Leder, P. Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54, 105–115 (1988)

    Article  CAS  Google Scholar 

  9. Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004)

    Article  CAS  Google Scholar 

  10. Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C. Pyruvate kinase M2 is a phosphotyrosine binding protein. Nature doi: 10.1038/nature06667 (this issue)

  11. Zheng, L., Roeder, R. G. & Luo, Y. S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell 114, 255–266 (2003)

    Article  CAS  Google Scholar 

  12. Stetak, A. et al. Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res. 67, 1602–1608 (2007)

    Article  CAS  Google Scholar 

  13. DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007)

    Article  CAS  ADS  Google Scholar 

  14. Manes, N. P. & El-Maghrabi, M. R. The kinase activity of human brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is regulated via inhibition by phosphoenolpyruvate. Arch. Biochem. Biophys. 438, 125–136 (2005)

    Article  CAS  Google Scholar 

  15. Telang, S. et al. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 25, 7225–7234 (2006)

    Article  CAS  Google Scholar 

  16. Vander Heiden, M. G. et al. Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol. Cell. Biol. 21, 5899–5912 (2001)

    Article  CAS  Google Scholar 

  17. Budinger, G. R. et al. Cellular energy utilization and supply during hypoxia in embryonic cardiac myocytes. Am. J. Physiol. 270, L44–L53 (1996)

    CAS  PubMed  Google Scholar 

  18. Sabatine, M. S. et al. Metabolomic identification of novel biomarkers of myocardial ischemia. Circulation 112, 3868–3875 (2005)

    Article  CAS  Google Scholar 

  19. Engelman, J. A. et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J. Clin. Invest. 116, 2695–2706 (2006)

    Article  CAS  Google Scholar 

  20. Root, D. E., Hacohen, N., Hahn, W. C., Lander, E. S. & Sabatini, D. M. Genome-scale loss-of-function screening with a lentiviral RNAi library. Nature Methods 3, 715–719 (2006)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Bentires-Alj for the MMTV-NeuNT tissue lysates and W. Hahn for the lentiviral shRNA constructs. We thank S. Soltoff for use of the anaerobic chamber and oxygen electrode, and Q. Song for use of the hypoxia chamber. We thank I. Rhee and T. Yuan for help with the nude mouse injections. We thank M. Liu for technical assistance. R.E.G. is supported by funding from the National Institutes of Health, the Donald W. Reynolds Foundation, the Fondation Leducq, and the Broad Institute Scientific Planning and Allocation of Resources Committee. M.G.V.H. is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation. This research was supported by funding to L.C.C. from the National Institutes of Health. S.L.S. is an Investigator with the Howard Hughes Medical Institute.

Author Contributions M.H.H. and M.D.F. contributed the immunohistochemistry data (Fig. 1c). A.R., R.E.G., R.W. and S.L.S. contributed the metabolite measurement data (Fig. 3d). H.R.C. and M.G.V.H. performed all other experiments. H.R.C., M.G.V.H. and L.C.C. designed the study and wrote the paper.

Author information

Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Heather R. Christofk, Matthew G. Vander Heiden & Lewis C. Cantley

  2. Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA,

    Matthew G. Vander Heiden

  3. Department of Pathology, Children’s Hospital, Boston, Massachusetts 02115, USA,

    Marian H. Harris & Mark D. Fleming

  4. Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA,

    Arvind Ramanathan, Robert E. Gerszten, Ru Wei & Stuart L. Schreiber

  5. Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts 02129, USA,

    Robert E. Gerszten

  6. Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Robert E. Gerszten

  7. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA,

    Stuart L. Schreiber

  8. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA,

    Lewis C. Cantley

Authors
  1. Heather R. Christofk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew G. Vander Heiden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marian H. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arvind Ramanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert E. Gerszten
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ru Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark D. Fleming
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stuart L. Schreiber
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lewis C. Cantley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lewis C. Cantley.

Ethics declarations

Competing interests

L.C.C. is a founder of a company (Cell Metabolism Therapeutics) that proposes to target enzymes in metabolism for cancer therapy. The results of this paper support this concept.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-2 with Legends. The Supplementary Figure 1 shows the peptide sequences used to generate PKM1- and PKM2-specific polyclonal antibodies as well as an immunoblot confirming antibody specificity. The Supplementary Figure 2 shows data from control experiments indicating that changes in PK activity in M1- and M2-expressing cells do not result in changes in adenine nucleotide levels. (PDF 193 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Christofk, H., Vander Heiden, M., Harris, M. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008). https://doi.org/10.1038/nature06734

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06734

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing