Abstract
The de novo serine synthesis pathway is upregulated in many cancers. However, even cancer cells with increased serine synthesis take up large amounts of serine from the environment1, and we confirm that exogenous serine is needed for maximal proliferation of these cells. Here we show that even when enzymes in the serine synthesis pathway are genetically upregulated, the demand for oxidized NAD+ constrains serine synthesis, rendering serine-deprived cells sensitive to conditions that decrease the cellular NAD+/NADH ratio. Further, purine depletion is a major consequence of reduced intracellular serine availability, particularly when NAD+ regeneration is impaired. Thus, cells rely on exogenous serine consumption to maintain purine biosynthesis. In support of this explanation, providing exogenous purine nucleobases, or increasing NAD+ availability to facilitate de novo serine and purine synthesis, rescues maximal proliferation even in the absence of extracellular serine. Together, these data indicate that NAD+ is an endogenous limitation for cancer cells to synthesize the serine needed for purine production to support rapid proliferation.
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Acknowledgements
We thank members of the Vander Heiden Lab for helpful discussions. We thank H. Furkan Alkan for providing the A549 shAGC1 cells. F.F.D. acknowledges support from the NIH (F31CA236036). M.G.V.H. acknowledges support from a Faculty Scholar grant from the Howard Hughes Medical Institute, SU2C, a division of the Entertainment Industry Foundation, the Lustgarten Foundation, the MIT Center for Precision Cancer Medicine, the Ludwig Center at MIT and the NIH (R01CA201276, R01CA168653 and P30CA14051).
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F.F.D. performed most experiments. F.F.D. and C.A.L. performed metabolite tracing experiments and LCMS data analysis. B.P.F. and C.A.L. performed the [6-13C]glucose and [3-13C]serine tracing experiment. F.F.D. and M.G.V.H. designed the study and wrote the manuscript.
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The authors are aware of no direct conflicts with the topic of the paper; however M.G.V.H. discloses that he is a scientific advisor and/or shareholder of Agios Pharmaceuticals, Aeglea Biotherapeutics and Auron Therapeutics. B.P.F. discloses he is a founder of Mythic Therapeutics.
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Diehl, F.F., Lewis, C.A., Fiske, B.P. et al. Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation. Nat Metab 1, 861–867 (2019). https://doi.org/10.1038/s42255-019-0108-x
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DOI: https://doi.org/10.1038/s42255-019-0108-x
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