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

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Abstract
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. Many tumour cells express the M2 form of pyruvate kinase rather than the usual M1 form. PKM2 is now shown to promote tumorigenesis and switch the cellular metabolism to increased lactate production and reduced oxygen consumption, recapitulating key aspects of the Warburg effect. 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.