Serine starvation induces stress and p53 dependent metabolic remodeling in cancer cells

By O. Maddocks, C. Berkers, S. Mason, Liang Zheng, K. Blyth, Eyal Gottlieb, Karen H. Vousden. Nature, 2012

933 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/9b2695e86c820cb3a28a2afb03addd54c37a6d5f

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Citations in the corpus

Understanding the intersections between metabolism and cancer biology (2017, positive): “Modulating the amino acid composition of the diet can slow cancer growth (Maddocks et al., 2013) and investigations into how diet affects tumor growth remains an underexplored area.”
One-Carbon Metabolism in Health and Disease. (2017, background): “…in cultured cancer cell lines due to a combination of excess methionine and the lack of cobalamin in standard tissue culture media (Maddocks et al., 2016). p53 / cells cultured without serine are deficient in growth, as are tumors in mice fed serine/glycine-free diets (Maddocks et al., 2013).”
Targeting Metabolism for Cancer Therapy (2017, background): “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…”
Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “255,256 Additionally, p53 directly binds to dipeptidyl-peptidase-4 (DPP4), blocking its activity, thus inhibiting DPP4/ NADPH oxidase 1 (NOX1) complex-mediated lipid peroxidation and erastin-induced ferroptosis.”
Gut microbiota modulation of chemotherapy efficacy and toxicity (2017, positive): “Nutritional modulation of cancer metabolism is also an emerging therapeutic approach, with fasting 68,69 , carbohydrate restriction 70 , amino acid restriction (L-asparaginase 71 , methionine 72 , serine 73 , tyrosine and phenylalanine 74 ) and ketogenic diets 75 under investigation.”
Metabolic control of cell death (2014, background): “Cells in which p53 functions are compromised (such as many cancer cells) succumb to serine-glycine or glutamine deprivation (104, 105), suggesting that p53 actually suppresses (rather than activates) cell death in these settings.”