Abstract C151: Contribution of serine, folate, and glycine metabolism to the ATP, NADPH, and purine requirements of cancer cells.

Abstract

Abstract Background: Recent observations on cancer cell metabolism indicate increased serine synthesis from glucose as a marker of poor prognosis. Expression of genes in this pathway also correlate with sensitivity to the antifolate methotrexate (Vazquez A, et al, Cancer Res. 2013 Jan 15;73(2):478-82). Using a large-scale model of human cell metabolism we have predicted that serine synthesis can be routed to a pathway for ATP production. The pathway is composed by reactions from the serine synthesis, one carbon (folate) metabolism and the glycine cleavage system (SOG pathway) and its flux is predicted to increase at high proliferation rates. Results: Here we show that the SOG pathway is upregulated at the level of gene expression in a subset of human tumors and its level of expression correlates with gene signatures of cell proliferation and Myc targets activation. To investigate the activity of the SOG pathway at the level of metabolic fluxes we estimated the metabolic fluxes of the NCI60 panel of tumor derived cell lines, using previously reported exchange fluxes and a flux balance model of cell metabolism. We show that the estimated rates of reactions in the SOG pathway are highly correlated with the proliferation rates of these cell lines. We also find that the SOG pathway contributes significantly to the energy requirements of biosynthesis, the NADPH requirements of fatty acid synthesis and to the synthesis of purines. Finally, when the PC-3 prostate cancer cell line is subject to treatment with the antifolate methotrexate, we observe a decrease in the ATP levels, an inhibition of the proliferation rate and a decrease in the ribonucleotides and fatty acids synthesized from glucose. Conclusions: 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. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C151. Citation Format: Philip M. Tedeschi, Elke K. Markert, Murugesan Gounder, HongXia Lin, Sonia C. Dolfi, Leo Li-Ying Chan, Jean Qiu, Kim M. Hirshfield, Laszlo G. Boros, Joseph R. Bertino, Zoltan N. Oltvai, Alexei Vazquez. Contribution of serine, folate, and glycine metabolism to the ATP, NADPH, and purine requirements of cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C151.