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, 4 (10), e877

Contribution of Serine, Folate and Glycine Metabolism to the ATP, NADPH and Purine Requirements of Cancer Cells

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Contribution of Serine, Folate and Glycine Metabolism to the ATP, NADPH and Purine Requirements of Cancer Cells

P M Tedeschi et al. Cell Death Dis.

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-(13)C2]-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.

Figures

Figure 1
Figure 1
The serine, one-carbon cycle, glycine synthesis (SOG) pathway. Schematic representation of the reactions involved in the SOG pathway, including serine synthesis (green), one-carbon cycle (red) and GC (blue) and the crosstalk with other pathways. The reaction directions are deduced from the inferred fluxes in the NCI60 panel of tumor-derived cell lines (see text for details)
Figure 2
Figure 2
Expression of genes encoding for enzymes in the SOG pathway in human cancers, differentiated cells and embryonic stem cells. Expression of genes encoding for enzymes in the SOG pathway (rows) across (a) breast and (b) prostate cancer patients (columns), based on data from and, respectively. The top rows display the SOG pathway, Myc target activation and proliferation gene signature upregulation scores as quantified by GSEA, together with the Myc gene expression. Blue color denotes under-expression and red color represents overexpression. The upper bar indicates the subset of tumors, where the SOG pathway signature is significantly downregulated (P<0.05, down), intermediate or significantly upregulated (P<0.05, up). (c) Expression of genes encoding for enzymes in the SOG pathway in human embryonic and differentiated normal cells, based on data reported in. (d) Expression of genes encoding for enzymes in the SOG pathway during differentiation of mouse R1 embryonic stem cell, based on data reported in. The samples are labeled by the day from initiation and by the condition used: embryonic body (EB) formation in non-adherent plastic dishes, gelatin coated plates (GEL) and matrigel coated plates (MAT). The white squares represent missing expression data
Figure 3
Figure 3
Metabolic fluxes as a function of the proliferation rate. (ai) Estimated metabolic fluxes of reactions in the SOG pathway are shown as a function of the proliferation rates of cell lines. Each point/error bar represents a cell line in the NCI60 panel. The point represents the median over the range of model kinetic parameters explored, and the error bars represent the 90% confidence intervals. The dashed lines are linear fits. Panels (b and e) report exchange fluxes as measured in. These fluxes are fixed in the personalized models and, therefore, they do not display error bars due to variations in the model kinetic parameters
Figure 4
Figure 4
Crosstalk with other pathways. (ai) Estimated rates of selected reactions that are part or crosstalk with the SOG pathway as a function of the proliferation rates of cell lines. Each point/error bar represents a cell line in the NCI60 panel. The point represents the median over the range of kinetic parameters explored and the error bars represent the 90% confidence intervals
Figure 5
Figure 5
The effect of methotrexate treatment on metabolic parameters. (a) PC-3 cell count as a function of time in cell cultures untreated and treated with 10 and 100 nM of methotrexate. (bf) Changes in (b) ATP, (c) ADP and (d) AMP levels and in (e) ADP/ATP and (f) AMP/ATP ratios following treatment with 100 nM methotrexate. (g) Western blots of AMPK, pAMPK, ACC and pACC following treatment with 100 nM methotrexate. (h) Quantification of the pAMPK/AMPK and pACC/ACC ratio relative to control (time zero data). (i) EZTopolome (heatmap) summarizing the changes in labeled metabolites measured in triplicate, in cell cultures untreated (control) and treated with 100 nM methotrexate (MTX). Red/blue indicates expression above/below the mean across samples. The top row indicates the color code for expression level changes

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