Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation
Open accessAbstract
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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Electron shuttles facilitate oxidation of cytosolic NADH, which is required to support continued glycolysis and de novo synthesis of serine and lipids.
“Beyond supporting net NADH “import” into the mitochondria, these shuttles also facilitate the oxidation of cytosolic NADH, which is required to support continued glycolysis and the de novo synthesis of serine and lipids (101, 102, 103).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [102]
PSPH-mediated serine synthesis is upregulated in cancer cells as a mechanism contributing to enhanced nucleotide and amino acid synthesis and antioxidant production, and is a potential novel therapeutic target for treating cancers.
“It is upregulated in cancer cells as a mechanism contributing to enhanced nucleotide and amino acid synthesis with regard to cell proliferation and antioxidant production, and it is a potential novel therapeutic target for treating cancers [29–31].”
From Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells (2022) · cites this paper as [30]
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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)
- Venue
- Nature Metabolism
- Published
- 2019-09-16
- Volume
- 1
- Issue
- 9
- Pages
- 861-867
- ISSN
- 2522-5812 (ISSN-L)
- 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
- 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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