Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells

Abstract

Recent observations on cancer cell metabolism indicate increased serine synthesis from glucose as a marker of poor prognosis. We have predicted that a fraction of the synthesized serine is routed to a pathway for ATP production. The pathway is composed by reactions from serine synthesis, one-carbon (folate) metabolism and the glycine cleavage system (SOG pathway). Here we show that the SOG pathway is upregulated at the level of gene expression in a subset of human tumors and that its level of expression correlates with gene signatures of cell proliferation and Myc target activation. We have also estimated the SOG pathway metabolic flux in the NCI60 tumor-derived cell lines, using previously reported exchange fluxes and a personalized model of cell metabolism. We find that the estimated rates of reactions in the SOG pathway are highly correlated with the proliferation rates of these cell lines. We also observe that the SOG pathway contributes significantly to the energy requirements of biosynthesis, to the NADPH requirement for fatty acid synthesis and to the synthesis of purines. Finally, when the PC-3 prostate cancer cell line is treated with the antifolate methotrexate, we observe a decrease in the ATP levels, AMP kinase activation and a decrease in ribonucleotides and fatty acids synthesized from [1,2-13C2]-D-glucose as the single tracer. Taken together our results indicate that the SOG pathway activity increases with the rate of cell proliferation and it contributes to the biosynthetic requirements of purines, ATP and NADPH of cancer cells.

Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk

“…circulating levels of components of one-carbon metabolism need not necessarily reflect intracellular conditions in all types of cells, and even less relative distributions between intracellular compartments, such as the cytoplasm and mitochondria. 11 rather, plasma levels are related to nutritional intake and cellular supply. it is thus conceivable that the relative contribution of methionine and betaine as one-carbon unit donors may be more pronounced in populations with low natural folate intake.…”

“…Folate, choline, betaine, and methionine all contribute to the availability of one-carbon units. 9,11 However, whereas folate is important for both nucleotide synthesis and methylation reactions, the role of choline, betaine, and methionine is limited to folate-independent remethylation pathways, where they may gain importance in the presence of low folate status. 38 Still, betaine is a relatively weak determinant of total homocysteine concentrations.…”

“…4,7 a greater understanding of the relative contribution of components in the one-carbon metabolism, including methionine and factors in the choline oxidation pathway, to colorectal cancer risk may therefore provide new insight into the mechanistic role of onecarbon metabolism in carcinogenesis. 11 to the best of our knowledge, only two previous prospective studies of colorectal cancer, nested within the european Prospective investigation into cancer and nutrition (ePic) cohort and the Women's Health initiative (WHi), 12,13 and one cross-sectional study of colorectal adenoma, 14 have addressed the role of circulating one-carbon metabolites other than folate in colorectal cancer development. inverse risk associations for betaine and null results for choline were observed in all three studies, [12][13][14] and an inverse association to colorectal cancer for methionine was reported in the ePic study.…”

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

“…Interestingly, it has been reported recently that these two amino acids play important roles in cancer progression [13][14][15][16]. Glycolytic metabolism of glucose provides metabolite of 3-PG which can be catalyzed by 3-phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1) and phosphoserine phosphatase (PSPH) into serine, during which glycine is produced through the inter-conversion between serine and glycine by serine hydroxymethyltransferase (SHMT1/2) [17][18][19].…”

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

“…[6][7][8][9] Recently, we have identified a fundamental connection between melanoma invasion and biosynthesis of guanylates, 8 suggesting that distortion of the guanylate metabolism facilitates melanoma progression.…”