title: 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-(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.
authors.affiliation: 1] Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA [2] Department of Pharmacology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Tedeschi
authors.forename: E K
authors.initials: EK
authors.lastname: Markert
authors.forename: M
authors.initials: M
authors.lastname: Gounder
authors.forename: H
authors.initials: H
authors.lastname: Lin
authors.forename: D
authors.initials: D
authors.lastname: Dvorzhinski
authors.forename: S C
authors.initials: SC
authors.lastname: Dolfi
authors.forename: L L-Y
authors.initials: LL
authors.lastname: Chan
authors.forename: J
authors.initials: J
authors.lastname: Qiu
authors.forename: R S
authors.initials: RS
authors.lastname: DiPaola
authors.forename: K M
authors.initials: KM
authors.lastname: Hirshfield
authors.forename: L G
authors.initials: LG
authors.lastname: Boros
authors.forename: J R
authors.initials: JR
authors.lastname: Bertino
authors.forename: Z N
authors.initials: ZN
authors.lastname: Oltvai
authors.forename: A
authors.initials: A
authors.lastname: Vazquez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000594:Amino Acid Oxidoreductases / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D053595:Embryonic Stem Cells / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D008297:Male; D064688:Metabolic Flux Analysis; D053858:Metabolic Networks and Pathways; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics; D009249:NADP / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D011687:Purines / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D014166:Transferases / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D005227:Fatty Acids; D009097:Multienzyme Complexes; D011687:Purines; C064525:glycine cleavage system; D012694:Serine; D009249:NADP; D000255:Adenosine Triphosphate; D005492:Folic Acid; D000594:Amino Acid Oxidoreductases; D014166:Transferases; D005998:Glycine; C030985:purine; D008727:Methotrexate