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

Abstract

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.

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Dihydrofolate reductase provides THF, which is a precursor to 5,10-methylene-THF. On the other hand, the proliferation defect induced by the knockdown of amplified 3-phosphoglycerate dehydrogenase in triple-negative breast cancers could not be rescued with the supplementation of extracellular serine [42,43], despite the fact that extracellular serine can fuel folate metabolism [50]. Thus, increased supply of serine does not seem to be the critical function of 3-phosphglycerate dehydrogenase amplification.…”

Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment

“…Recently, a number of studies have assessed the significance of serine and glycine metabolism in cancer cells. The complex, cyclical nature of serine and glycine metabolism can occur through cytoplasmic and mitochondrial pathways, both of which have been demonstrated to be upregulated in cancer cells (46)(47)(48)(49)(50). Additionally, serine and glycine metabolism converge on the formation of folate compounds, a target of chemotherapy for over sixty years (51)(52)(53).…”

Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion

“…A recent study has suggested that cancer cells rely more on serine than glycine to support growth and metabolism 20 . A similar trend was observed in the five breast cancer cell lines we examined; serine supplementation of basal media enhanced the growth of all the cell lines, glycine supplementation increased growth of only one cell line, while formate did not affect the growth of any of the cell lines examined (Suppl.…”