Evidence for an alternative glycolytic pathway in rapidly proliferating cells

By M. V. Vander Heiden, Jason W. Locasale, K. Swanson, Hadar Sharfi, G. Heffron, D. Amador-Noguez, H. Christofk, G. Wagner, Joshua D. Rabinowitz, J. Asara and 1 more. Science, 2010

645 citations recorded by the source corpus.

Glucose Metabolism Revisited Cancer cells are revved up to reproduce rapidly and typically consume glucose rapidly by glycolysis. Why then do cancer cells express an isoform of a rate-limiting enzyme in glycolysis, pyruvate kinase M2, which has decreased activity? Vander Heiden et al. (p. 1492) propose that consequent accumulation of phosphoenolpyruvate, with the help of an enzymatic activity that remains to be characterized, can lead to phosphate transfer to phosphoglycerate mutase, another glycolytic enzyme, providing the cell with a different way to make pyruvate. This may allow cancer cells to produce pyruvate without generating excess adenosine triphosphate, which can act through feedback to inhibit glycolyis. Characterization of cancer cell metabolism provides evidence for a previously uncharacterized metabolic pathway. Proliferating cells, including cancer cells, require altered metabolism to efficiently incorporate nutrients such as glucose into biomass. The M2 isoform of pyruvate kinase (PKM2) promotes the metabolism of glucose by aerobic glycolysis and contributes to anabolic metabolism. Paradoxically, decreased pyruvate kinase enzyme activity accompanies the expression of PKM2 in rapidly dividing cancer cells and tissues. We demonstrate that phosphoenolpyruvate (PEP), the substrate for pyruvate kinase in cells, can act as a phosphate donor in mammalian cells because PEP participates in the phosphorylation of the glycolytic enzyme phosphoglycerate mutase (PGAM1) in PKM2-expressing cells. We used mass spectrometry to show that the phosphate from PEP is transferred to the catalytic histidine (His11) on human PGAM1. This reaction occurred at physiological concentrations of PEP and produced pyruvate in the absence of PKM2 activity. The presence of histidine-phosphorylated PGAM1 correlated with the expression of PKM2 in cancer cell lines and tumor tissues. Thus, decreased pyruvate kinase activity in PKM2-expressing cells allows PEP-dependent histidine phosphorylation of PGAM1 and may provide an alternate glycolytic pathway that decouples adenosine triphosphate production from PEP-mediated phosphotransfer, allowing for the high rate of glycolysis to support the anabolic metabolism observed in many proliferating cells.

Subfields: Biochemistry, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7ad1bd3392c5f940ff6cf943c3470cbd3400b5ad

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Citations in the corpus

PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis (2012, positive): “In Vitro Kinase Assays The kinase reactions were performed as described previously (Fang et al., 2007; Vander Heiden et al., 2010).”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “One way to get around the PKM2 bottleneck and maintain/enhance pyruvate production may be through a proposed alternative glycolytic pathway involving an enzymatic activity not yet purified that dephosphorylates PEP to pyruvate without the generation of ATP (Vander Heiden et al., 2010).”
Lactate: a metabolic key player in cancer. (2011, background): “However, PEP can also serve as a phosphor donor for phosphoglycerate mutase 1 (PGAM1), leading to the formation of pyruvate independently of PKM2 activity (8).”
Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. (2012, positive): “Recent studies have led to an emerging appreciation of the importance of metabolic reprogramming in cancer (Hsu and Sabatini, 2008; Vander Heiden et al., 2009; Hanahan andWeinberg, 2011).”
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses (2015, background): “…because of the above inhibitor studies and because TCR activation increases expression of the less-active M2 isoform of pyruvate kinase (PKM2) (Wang et al., 2011a), which allows the accumulation of several metabolic intermediates, including PEP, in proliferating cells (Vander Heiden et al., 2010).”
The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis (2011, background): “The AR regulates aerobic glycolysis and anabolism in prostate cancer cells Androgen stimulation of prostate cancer cells increased glucose uptake and increased lactate production in normoxia, but had no effect on oxygen consumption, showing that AR signalling does indeed stimulate aerobic glycolysis”
Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “Despite the expression of protein, the enzyme activity of PKM2 can be decreased in rapidly dividing cancer cells [140].”
Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “It is worth noting however, that while PKM2 is not necessarily selected for specifically in proliferating cells, the expression of PKM1 in such cells is essentially absent or detected at only very low levels (141).”