Article

Evidence for an Alternative Glycolytic Pathway in Rapidly Proliferating Cells

Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Science (Impact Factor: 31.48). 09/2010; 329(5998):1492-9. DOI: 10.1126/science.1188015
Source: PubMed

ABSTRACT 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.

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    • "Although PEP could inhibit SERCA activity and increase its oxidative state, the precise molecular mechanism(s) by which this occurs remains unknown. Possibly PEP directly conjugates to or oxidizes cysteine residues on SERCA or alternatively PEP could serve as a high-energy phosphate donor to phosphorylate SERCA or other proteins that inhibit its activity (Vander Heiden et al., 2010). Future biochemical studies are needed to precisely characterize which residues in SERCA, if any, are modified by PEP. "
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    • "Both glucose (Glc) and glutamine (Gln) have been shown to support cancer cell growth; however, the linkage between cancer cells' invasive and migratory potential and metabolic dependencies are not well studied and thus less appreciated. There is mounting evidence on the dynamic interactions of glucose metabolism with cancer cell's survival pathways implicating invasion, migration and energetic homeostasis (Vander Heiden et al, 2010; Locasale & Cantley, 2011; Graham et al, 2012; Komurov et al, 2012). Many glycolysis targeting drugs modulate cellular differentiation, antiapoptotic response and metastasis (Turkson & Jove, 2000; Levy & Lee, 2002; Schindler et al, 2007) through activation pathways which include epidermal growth factor receptor (EGFR) kinase, Src, Janus-activated kinase (JAK) and extracellular signal-regulated kinase (ERK; Chung et al, 1997; Garcia et al, 1997, 2001; Yu et al, 2003; Schindler et al, 2007). "
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    • "The predominant lactate fraction, i.e. M + 3, increased to 0.85 and the pyruvate M + 3 fraction stabilized at 0.81, pointing towards glycolytic channeling to lactate achieved by the localized cooperation of glycolytic enzymes as observed in rapidly proliferating cells [39,40]. From the produced amino acids, alanine, also derived from pyruvate, had a high M + 3 fraction. "
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