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


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.

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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.

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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.

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Correspondence to Lewis C. Cantley.

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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.

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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)

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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).

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