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.
Highlights
Has a larger energy yield and it is the major pathway in normal cells under normal oxygen tension
The analysis of gene expression data across human cancers indicates that the expression of genes coding for enzymes in the serine synthesis (SOG) pathway is correlated with gene signatures of cell proliferation and Myc target activation, as previously shown in vitro.[11]
The association between SOG pathway activity and cell proliferation is further supported at the level of metabolic fluxes of cancer cell lines grown in vitro
Summary
Has a larger energy yield and it is the major pathway in normal cells under normal oxygen tension. The glycolysis flux can be diverted from the glycolysis intermediate 3-phosphoglycerate toward serine synthesis, as first demonstrated in lymphomas.[5] More recently, it has been reported that the flux toward serine synthesis is upregulated in breast cancer[6,7] and melanoma.[8] Studies in melanoma revealed that a significant portion of the serine produced is converted to glycine.[8] Glycine can enter the glycine cleavage (GC) system, where it is converted to ammonium and methylene tetrahydrofolate (THF), the coenzyme for thymidylate synthesis.[5] More recently glycine metabolism has been shown to be upregulated in non-small cell lung cancers[9,10] and highly proliferating tumor-derived cell lines.[11] In parallel to these experimental discoveries, we have recently developed a large-scale model of human cell metabolism that has provided new insights into the advantages of metabolic alterations in cancer cells.[12,13,14] We have shown that glycolysis has a higher rate of ATP production per mass of pathway enzymes than OxPhos.[12,13] at high proliferation rates, when the cytosol is overcrowded with ribosomes and metabolic enzymes, glycolysis is more
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