The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
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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Decreased pyruvate kinase activity is associated with increased aerobic glycolysis.
“Paradoxically, decreased pyruvate kinase activity is associated with increased aerobic glycolysis, suggesting the activation of pyruvate kinase activity might be a way to target cancer (Christofk et al., 2008).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Christofk et al., 2008
Tumor cells engineered to exclusively express M2 isoform display increased lactate production characteristic of Warburg effect and gain growth advantage in vivo over M1-expressing tumors.
“Tumor cells engineered to exclusively express the M2 isoform display increased lactate production characteristic of the Warburg effect and gain a growth advantage in vivo over M1-expressing tumors (57).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [57]
PKM2 promotes the Warburg effect and tumorigenesis.
“PKM2 promotes the Warburg effect and tumorigenesis (Christofk et al., 2008; Hitosugi et al., 2009).”
From Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1 (2011) · cites this paper as Christofk et al., 2008
PKM2, when highly expressed, exists in an equilibrium of enzymatically inactive pyruvate kinase dimers (or monomers) which can translocate into the nucleus, and enzymatically active tetramers which are retained in the cytosol.
“Current data indicates that PKM2, when highly expressed, exists in an equilibrium of enzymatically inactive pyruvate kinase dimers (or monomers) which can translocate into the nucleus(Christofk et al., 2008; Hitosugi et al., 2009), and enzymatically active tetramers which are retained in the cytosol(Mazurek et al., 2005).”
From Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages (2015) · cites this paper as Christofk et al., 2008
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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
- Venue
- Nature
- Published
- 2008-03
- Volume
- 452
- Issue
- 7184
- Pages
- 230-233
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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