Cited by 159Cancer, Hypoxia, and MetabolismBiochemical and Molecular ResearchAmino Acid Enzymes and Metabolism

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Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation

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Diehl, Frances F., Lewis, Caroline A., Fiske, Brian P., Vander Heiden, Matthew G.·2019·Nature Metabolism

DOI 10.1038/s42255-019-0108-xPMC PMC6785045

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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, both rescue 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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Authors: Diehl, F. F., Lewis, C. A., Fiske, B. P., & Vander Heiden, M. G.
Affiliations: Koch Institute for Integrative Cancer Research At MIT (US)
Whitehead Institute for Biomedical Research (US)
ORCID: Lewis, Caroline A.
Fiske, Brian P.
Vander Heiden, Matthew G.
Venue: Nature Metabolism
Publisher: Springer Science and Business Media LLC
Published: 2019-09-16
Volume: 1
Issue: 9
Pages: 861-867
ISSN: 2522-5812 (ISSN-L)
DOI: 10.1038/s42255-019-0108-x
PMC: PMC6785045
OpenAlex: W2973847049
Cited by: 159
References: 26
Citations by year: 2026: 17 · 2025: 15 · 2024: 26 · 2023: 18 · 2022: 24 · 2021: 28 · 2020: 28 · 2019: 3
FWCI: 6.96
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
PMC
Funders: U.S. Department of Health & Human Services | NIH | National Cancer Institute (F31CA236036, T32MH096678, R01CA201276, R01CA168653, P30CA14051)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: de novo serine synthesis, NAD+/NADH ratio, redox state, purine biosynthesis, nucleotide production, cell proliferation, cancer metabolism, NAD+ regeneration, purine nucleobases
MeSH terms: Humans, Neoplasms, Nucleotides, Oxidation-Reduction, Serine, Cell Proliferation

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Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation

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