Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells
Open accessAbstract
Cancer cells acquire distinct metabolic adaptations to survive stress associated with tumour growth and to satisfy the anabolic demands of proliferation. The tumour suppressor protein p53 (also known as TP53) influences a range of cellular metabolic processes, including glycolysis, oxidative phosphorylation, glutaminolysis and anti-oxidant response. In contrast to its role in promoting apoptosis during DNA-damaging stress, p53 can promote cell survival during metabolic stress, a function that may contribute not only to tumour suppression but also to non-cancer-associated functions of p53. Here we show that human cancer cells rapidly use exogenous serine and that serine deprivation triggered activation of the serine synthesis pathway and rapidly suppressed aerobic glycolysis, resulting in an increased flux to the tricarboxylic acid cycle. Transient p53-p21 (also known as CDKN1A) activation and cell-cycle arrest promoted cell survival by efficiently channelling depleted serine stores to glutathione synthesis, thus preserving cellular anti-oxidant capacity. Cells lacking p53 failed to complete the response to serine depletion, resulting in oxidative stress, reduced viability and severely impaired proliferation. The role of p53 in supporting cancer cell proliferation under serine starvation was translated to an in vivo model, indicating that serine depletion has a potential role in the treatment of p53-deficient tumours.
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Certain tumors are dependent on uptake of environmental serine.
“Certain tumors are dependent on uptake of environmental serine (Jain et al., 2012; Maddocks et al., 2013; Maddocks et al., 2017), and limiting plasma serine availability can be beneficial for patients with these cancers.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Maddocks et al., 2013
Serine deprivation by dietary restriction is sufficient to slow growth of both xenograft and autochthonous cancer models, although efficacy is influenced by the oncogenic driver mutation and tissue context.
“Additionally, serine deprivation by dietary restriction is sufficient to slow growth of both xenograft (Gravel et al., 2014; Maddocks et al., 2013) and autochthonous cancer models, although efficacy of serine deprivation appears to be influenced by both the oncogenic driver mutation and tissue context (Maddocks et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Maddocks et al., 2013
Combining serine restriction with other drugs may potentiate antitumor responses.
“Combining serine restriction with other drugs may also potentiate antitumor responses (Gravel et al., 2014; Maddocks et al., 2013; Maddocks et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Maddocks et al., 2013
Serine production is of particular significance because serine is a major substrate for the folate/one-carbon cycle whose metabolites contribute to various cellular biosynthetic and regulatory processes.
“Of particular significance is serine production because it is a major substrate for the folate/one-carbon cycle whose metabolites contribute to various cellular biosynthetic and regulatory processes (212, 213).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [212]
In mice, colon cancer xenografts grow less when serine and glycine are absent from the diet.
“Indeed, dietary serine and glycine deficiency has been shown to impair xenograft growth of colon cancer cells in mice (Maddocks et al., 2013).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Maddocks et al., 2013
Cancer cells actively produce GSH from glucose via the SBP as a buffer against oxidative damage.
“Recent evidence indicates that cancer cells actively produce GSH from glucose via the SBP as a buffer against oxidative damage (67).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [67]
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 [29]
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- Authors
- Maddocks, O. D. K., Berkers, C. R., Mason, S. M., Zheng, L., Blyth, K., Gottlieb, E., & Vousden, K. H.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Corresponding author
- Vousden, Karen H.
- ORCID
- Venue
- Nature
- Published
- 2012-12-16
- Volume
- 493
- Issue
- 7433
- Pages
- 542-546
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6485472
- OpenAlex
- W1980181091
- Cited by
- 1,007
- References
- 33
- Citations by year
- 2026: 51 · 2025: 78 · 2024: 77 · 2023: 89 · 2022: 88 · 2021: 103 · 2020: 97 · 2019: 68 · 2018: 65 · 2017: 54 · 2016: 84 · 2015: 55 · 2014: 64 · 2013: 34
- FWCI
- 16.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cancer Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p53, cancer metabolism, metabolic remodeling, serine biosynthesis, glutathione synthesis, reactive oxygen species, oxidative stress, aerobic glycolysis, TCA cycle, p21, cell cycle arrest, tumor growth inhibition
- MeSH terms
- Aerobiosis, Animals, Antioxidants, Cell Survival, Cells, Cultured, Citric Acid Cycle, Disease Models, Animal, Energy Metabolism, Female, Glutathione, Glycolysis, Humans, Neoplasm Transplantation, Neoplasms, Nucleotides, Promoter Regions, Genetic, Serine, Starvation, Tumor Suppressor Protein p53, G1 Phase, Oxidative Stress, HCT116 Cells, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Mice, Cell Cycle Checkpoints
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