nature.com

Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis - Nature Genetics

  • ️Vander Heiden, Matthew G
  • ️Sun Jul 31 2011

References

  1. Vander Heiden, M.G., Cantley, L.C. & Thompson, C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  Google Scholar 

  2. DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G. & Thompson, C.B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11–20 (2008).

    Article  CAS  Google Scholar 

  3. Warburg, O., Posener, K. & Negelein, E. Ueber den Stoffwechsel der Tumoren. Biochem. Z. 152, 319–344 (1924).

    Google Scholar 

  4. Bodenhausen, G. & Ruben, D.J. Natural abundance nitrogen-15 NMR by enhanced heteronuclear spectroscopy. Chem. Phys. Lett. 69, 185–189 (1980).

    Article  CAS  Google Scholar 

  5. Bismut, H., Caron, M., Coudray-Lucas, C. & Capeau, J. Glucose contribution to nucleic acid base synthesis in proliferating hepatoma cells: a glycine-biosynthesis-mediated pathway. Biochem. J. 308, 761–767 (1995).

    Article  CAS  Google Scholar 

  6. Snell, K., Natsumeda, Y. & Weber, G. The modulation of serine metabolism in hepatoma 3924A during different phases of cellular proliferation in culture. Biochem. J. 245, 609–612 (1987).

    Article  CAS  Google Scholar 

  7. Kit, S. The biosynthesis of free glycine and serine by tumors. Cancer Res. 15, 715–718 (1955).

    CAS  PubMed  Google Scholar 

  8. de Koning, T.J. et al. L-serine in disease and development. Biochem. J. 371, 653–661 (2003).

    Article  CAS  Google Scholar 

  9. Achouri, Y., Rider, M.H., Van Schaftingen, E. & Robbi, M. Cloning, sequencing and expression of rat liver 3-phosphoglycerate dehydrogenase. Biochem. J. 323, 365–370 (1997).

    Article  CAS  Google Scholar 

  10. Lu, W., Bennett, B.D. & Rabinowitz, J.D. Analytical strategies for LC-MS-based targeted metabolomics. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 871, 236–242 (2008).

    Article  CAS  Google Scholar 

  11. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  Google Scholar 

  12. Greshock, J. et al. A comparison of DNA copy number profiling platforms. Cancer Res. 67, 10173–10180 (2007).

    Article  CAS  Google Scholar 

  13. Slamon, D.J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).

    Article  CAS  Google Scholar 

  14. Luo, J., Solimini, N.L. & Elledge, S.J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).

    Article  CAS  Google Scholar 

  15. Pollari, S. et al. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res. Treat. 125, 421–430 (2011).

    Article  CAS  Google Scholar 

  16. Foulkes, W.D., Smith, I.E. & Reis-Filho, J. Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948 (2010).

    Article  CAS  Google Scholar 

  17. Debnath, J. & Brugge, J.S. Modelling glandular epithelial cancers in three-dimensional cultures. Nat. Rev. Cancer 5, 675–688 (2005).

    Article  CAS  Google Scholar 

  18. Schafer, Z.T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).

    Article  CAS  Google Scholar 

  19. Tabatabaie, L. et al. Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. Hum. Mutat. 30, 749–756 (2009).

    Article  CAS  Google Scholar 

  20. Thompson, C.B. Metabolic enzymes as oncogenes or tumor suppressors. N. Engl. J. Med. 360, 813–815 (2009).

    Article  CAS  Google Scholar 

  21. Teperino, R., Schoonjans, K. & Auwerx, J. Histone methyl transferases and demethylases: can they link metabolism and transcription? Cell Metab. 12, 321–327 (2010).

    Article  CAS  Google Scholar 

  22. Nomura, D.K. et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140, 49–61 (2010).

    Article  CAS  Google Scholar 

  23. Hara, K. et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484–14494 (1998).

    Article  CAS  Google Scholar 

  24. Vander Heiden, M.G. et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329, 1492–1499 (2010).

    Article  CAS  Google Scholar 

  25. Locasale, J.W. & Cantley, L.C. Altered metabolism in cancer. BMC Biol. 8, 88 (2010).

    Article  Google Scholar 

  26. Eng, C.H., Yu, K., Lucas, J., White, E. & Abraham, R.T. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci. Signal. 3, ra31 (2010).

    PubMed  Google Scholar 

  27. Antoniewicz, M.R., Kelleher, J.K. & Stephanopoulos, G. Accurate assessment of amino acid mass isotopomer distributions for metabolic flux analysis. Anal. Chem. 79, 7554–7559 (2007).

    Article  CAS  Google Scholar 

  28. Fernandez, C.A., Des Rosiers, C., Previs, S.F., David, F. & Brunengraber, H. Correction of 13C mass isotopomer distributions for natural stable isotope abundance. J. Mass Spectrom. 31, 255–262 (1996).

    Article  CAS  Google Scholar 

  29. Richardson, A.L. et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9, 121–132 (2006).

    Article  CAS  Google Scholar 

  30. Hoek, K. et al. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res. 64, 5270–5282 (2004).

    Article  CAS  Google Scholar 

  31. Rhodes, D.R. et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6, 1–6 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Microscopy data for this study were acquired and analyzed in the Nikon Imaging Center at Harvard Medical School. J.W.L. was supported by postdoctoral fellowships from the US National Institutes of Health (NIH) and the American Cancer Society. A.R.G. is a recipient of a National Science Foundation (NSF) Graduate Research Fellowship. L.C.C. and J.S.B. were supported by grants from the NIH and the National Cancer Institute (NCI). M.G.V.H. was supported by grants from the NIH, NCI, Smith Family, Damon Runyon Cancer Research Foundation and the Burroughs Wellcome Fund. We thank N. Vena for technical assistance with the FISH analysis and K. Webster and I. Carrecedo for help with immunohistochemistry. We thank J. Rabinowitz, A. Carrecedo and S.-C. Ng for helpful comments on the manuscript.

Author information

Authors and Affiliations

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

    Jason W Locasale, Tamar Melman, Costas A Lyssiotis, Hadar Sharfi, Atsuo T Sasaki, Dimitrios Anastasiou, Edouard Mullarky, Mika Sasaki & Lewis C Cantley

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

    Jason W Locasale, Tamar Melman, Costas A Lyssiotis, Hadar Sharfi, Atsuo T Sasaki, Dimitrios Anastasiou, Edouard Mullarky, Mika Sasaki, John M Asara & Lewis C Cantley

  3. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    Alexandra R Grassian, Taru Muranen & Joan S Brugge

  4. Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Katherine R Mattaini, Natalie I Vokes & Matthew G Vander Heiden

  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Adam J Bass, Rameen Beroukhim, Azra H Ligon, Matthew Meyerson, Andrea L Richardson, Lynda Chin & Matthew G Vander Heiden

  6. Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Adam J Bass, Rameen Beroukhim & Matthew Meyerson

  7. Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Gregory Heffron & Gerhard Wagner

  8. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Christian M Metallo & Gregory Stephanopoulos

  9. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Rameen Beroukhim

  10. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Azra H Ligon & Andrea L Richardson

  11. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Matthew Meyerson

  12. Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA

    Lynda Chin

Authors

  1. Jason W Locasale

    You can also search for this author in PubMed Google Scholar

  2. Alexandra R Grassian

    You can also search for this author in PubMed Google Scholar

  3. Tamar Melman

    You can also search for this author in PubMed Google Scholar

  4. Costas A Lyssiotis

    You can also search for this author in PubMed Google Scholar

  5. Katherine R Mattaini

    You can also search for this author in PubMed Google Scholar

  6. Adam J Bass

    You can also search for this author in PubMed Google Scholar

  7. Gregory Heffron

    You can also search for this author in PubMed Google Scholar

  8. Christian M Metallo

    You can also search for this author in PubMed Google Scholar

  9. Taru Muranen

    You can also search for this author in PubMed Google Scholar

  10. Hadar Sharfi

    You can also search for this author in PubMed Google Scholar

  11. Atsuo T Sasaki

    You can also search for this author in PubMed Google Scholar

  12. Dimitrios Anastasiou

    You can also search for this author in PubMed Google Scholar

  13. Edouard Mullarky

    You can also search for this author in PubMed Google Scholar

  14. Natalie I Vokes

    You can also search for this author in PubMed Google Scholar

  15. Mika Sasaki

    You can also search for this author in PubMed Google Scholar

  16. Rameen Beroukhim

    You can also search for this author in PubMed Google Scholar

  17. Gregory Stephanopoulos

    You can also search for this author in PubMed Google Scholar

  18. Azra H Ligon

    You can also search for this author in PubMed Google Scholar

  19. Matthew Meyerson

    You can also search for this author in PubMed Google Scholar

  20. Andrea L Richardson

    You can also search for this author in PubMed Google Scholar

  21. Lynda Chin

    You can also search for this author in PubMed Google Scholar

  22. Gerhard Wagner

    You can also search for this author in PubMed Google Scholar

  23. John M Asara

    You can also search for this author in PubMed Google Scholar

  24. Joan S Brugge

    You can also search for this author in PubMed Google Scholar

  25. Lewis C Cantley

    You can also search for this author in PubMed Google Scholar

  26. Matthew G Vander Heiden

    You can also search for this author in PubMed Google Scholar

Contributions

J.W.L., M.G.V.H. and L.C.C. designed the study and wrote the paper. J.W.L., C.A.L., E.M., K.R.M., D.A., H.S., M.G.V.H. and T. Melman carried out experiments. J.W.L. and T. Melman carried out computational analyses. A.J.B., R.B. and M.M. provided help with copy number data. L.C. and A.L.R. provided human cancer samples. N.I.V. and A.H.L. carried out the FISH analysis. J.W.L. and J.M.A. carried out the LC/MS/MS experiments. J.W.L., G.H. and G.W. carried out the NMR experiments. J.W.L., N.I.V., C.M.M. and G.S. carried out the GC/MS experiments. M.S. and A.T.S. generated reagents. J.S.B., T. Muranen and A.R.G. carried out experiments involving acinar morphogenesis and imaging analysis.

Corresponding authors

Correspondence to Jason W Locasale, Lewis C Cantley or Matthew G Vander Heiden.

Ethics declarations

Competing interests

J.W.L., M.V.H. and L.C.C. are consultants, scientific advisors and part owners of Agios Pharmaceuticals and hold patents pertaining to targeting cellular metabolism for cancer treatment. Agios Pharmaceuticals is interested in developing therapeutics that target altered metabolism in cancer.

Supplementary information

About this article

Cite this article

Locasale, J., Grassian, A., Melman, T. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43, 869–874 (2011). https://doi.org/10.1038/ng.890

Download citation

  • Received: 19 July 2010

  • Accepted: 27 June 2011

  • Published: 31 July 2011

  • Issue Date: September 2011

  • DOI: https://doi.org/10.1038/ng.890