1. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
3. Department of Pathology, Children's Hospital, Boston, Massachusetts 02115, USA
4. Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
5. Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts 02129, USA
6. Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis, Harvard Medical School, Boston, Massachusetts 02115, USA
7. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA
8. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA

Correspondence to: Lewis C. Cantley^1,8 Correspondence and requests for materials should be addressed to L.C.C. (Email: lcantley@hms.harvard.edu).

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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