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

Heather R. Christofk, Matthew G. Vander Heiden, Marian H. Harris, Arvind Ramanathan, Robert E. Gerszten, Ru Wei, Mark D. Fleming, Stuart L. Schreiber and Lewis C. Cantley ()
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Heather R. Christofk: Harvard Medical School, Boston, Massachusetts 02115, USA
Matthew G. Vander Heiden: Harvard Medical School, Boston, Massachusetts 02115, USA
Marian H. Harris: Children’s Hospital, Boston, Massachusetts 02115, USA
Arvind Ramanathan: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
Robert E. Gerszten: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
Ru Wei: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
Mark D. Fleming: Children’s Hospital, Boston, Massachusetts 02115, USA
Stuart L. Schreiber: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
Lewis C. Cantley: Harvard Medical School, Boston, Massachusetts 02115, USA

Nature, 2008, vol. 452, issue 7184, 230-233

Abstract: The Warburg effect Metabolic regulation in rapidly growing tissues such as fetal tissue and tumours tends to differ from that in most normal adult tissues, and many tumour cells are known to express the M2 (fetal) form of the glycolysis pathway enzyme pyruvate kinase (PKM2) rather than the adult M1 isoform. Two linked papers in this issue focus on role of PKM2 in tumour cells. In the first, PKM2 was identified in a proteomic screen as a phosphotyrosine binding protein. Replacement of endogenous PKM2 with a point mutant that cannot bind phosphotyrosine slows the growth of cancer cells in culture, indicating that regulation of PKM2 via phosphotyrosine binding is essential for cancer cell proliferation. In the second paper, PKM2 is shown to promote tumorigenesis and to switch cellular metabolism to increased lactate production and reduced oxygen consumption. This pattern resembles aspects of the Warburg effect, Otto Warburg's observation, made in the 1930s, that many cancer cells produce energy by glycolysis followed by lactic acid fermentation in the cytosol, rather than by mitochondrial oxidation of pyruvate.

Date: 2008
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DOI: 10.1038/nature06734

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