Cited by 2,820Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerCancer and biochemical research

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

Christofk, Heather R., Vander Heiden, Matthew G., Harris, Marian H., Ramanathan, Arvind, Gerszten, Robert E., Wei, Ru, Fleming, Mark D., Schreiber, Stuart L., Cantley, Lewis C.·2008·Nature

DOI 10.1038/nature06734

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Abstract

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 ago. 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 kinase. 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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Authors: Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., & Cantley, L. C.
Affiliations: Harvard University (US)
Boston Children's Hospital (US)
Broad Institute (US)
Beth Israel Deaconess Medical Center (US)
Corresponding author: Cantley, Lewis C.
ORCID: Christofk, Heather R.
Harris, Marian H.
Ramanathan, Arvind
Gerszten, Robert E.
Wei, Ru
Fleming, Mark D.
Schreiber, Stuart L.
Cantley, Lewis C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2008-03
Volume: 452
Issue: 7184
Pages: 230-233
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature06734
OpenAlex: W2015207840
Cited by: 2,820
References: 20
Citations by year: 2026: 68 · 2025: 101 · 2024: 133 · 2023: 142 · 2022: 151 · 2021: 174 · 2020: 169 · 2019: 170 · 2018: 190 · 2017: 158 · 2016: 180 · 2015: 204 · 2014: 211 · 2013: 187 · 2012: 186
FWCI: 44.09
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Howard Hughes Medical Institute
National Cancer Institute (T32CA009172)
National Institute of General Medical Sciences (R01GM056203)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
Keywords: PKM2, alternative splicing, cancer metabolism, Warburg effect, aerobic glycolysis, carcinogenesis, phosphotyrosine binding, lactic acid production, oxygen consumption, glucose uptake, oxidative phosphorylation, tumor growth, glycolysis, tumor cell proliferation, tumor hypoxia
MeSH terms: Animals, Fructosediphosphates, Glycolysis, Humans, Lung Neoplasms, Male, Mice, Nude, Neoplasm Transplantation, Neoplasms, Oxidative Phosphorylation, Oxygen Consumption, Pyruvate Kinase, Gene Expression Regulation, Neoplastic, Alternative Splicing, Pyruvic Acid, Lactic Acid, Cell Line, Tumor, Cell Proliferation, Mice

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

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