Serine, but Not Glycine, Supports One-Carbon Metabolism and Proliferation of Cancer Cells

• Published in: Cell reports (Cambridge) 2014-05, Vol.7 (4), p.1248-1258
• Main Authors: Labuschagne, Christiaan F., van den Broek, Niels J.F., Mackay, Gillian M., Vousden, Karen H., Maddocks, Oliver D.K.
• Format: Article
• Language: English
• Subjects: Carbon - metabolism; Cell Growth Processes - physiology; Glycine - administration & dosage; Glycine - metabolism; Glycine - pharmacokinetics; HCT116 Cells; Humans; MCF-7 Cells; Metabolic Networks and Pathways; Neoplasms - metabolism; Neoplasms - pathology; Serine - administration & dosage; Serine - metabolism; Serine - pharmacokinetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.04.045

Previous work has shown that some cancer cells are highly dependent on serine/glycine uptake for proliferation. Although serine and glycine can be interconverted and either might be used for nucleotide synthesis and one-carbon metabolism, we show that exogenous glycine cannot replace serine to support cancer cell proliferation. Cancer cells selectively consumed exogenous serine, which was converted to intracellular glycine and one-carbon units for building nucleotides. Restriction of exogenous glycine or depletion of the glycine cleavage system did not impede proliferation. In the absence of serine, uptake of exogenous glycine was unable to support nucleotide synthesis. Indeed, higher concentrations of glycine inhibited proliferation. Under these conditions, glycine was converted to serine, a reaction that would deplete the one-carbon pool. Providing one-carbon units by adding formate rescued nucleotide synthesis and growth of glycine-fed cells. We conclude that nucleotide synthesis and cancer cell proliferation are supported by serine—rather than glycine—consumption. [Display omitted] •Many cancer cells consume serine in preference to glycine•Glycine cannot substitute for serine to support nucleotide synthesis•Excess glycine is converted to serine, consuming one-carbon units•Pulse Stop-Flux: a new method for detecting flux into low-abundance metabolites In this study, Labuschagne et al. examine how cancer cells utilize exogenous pools of the nonessential amino acids serine and glycine and find that glycine cannot substitute for serine to support cancer cell proliferation. Serine is a significant source of one-carbon units for purine synthesis, whereas glycine alone is unable to support nucleotide synthesis. The growth defect of cells fed glycine only was rescued by the addition of formate, which supplies one-carbon units for purine synthesis.