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Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.

ABSTRACT: Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. This effect is exacerbated by amino acid shortage, representing a mutant p53-dependent metabolic adaptive response. When cells suffer amino acids scarcity, mutant p53 protein is stabilized and induces metabolic alterations and an amino acid transcriptional program that sustain cancer cell proliferation. In patient-derived tumor organoids, pharmacological targeting of either serine-synthesis-pathway and LAT1-mediated transport synergizes with amino acid shortage in blunting mutant p53-dependent growth. These findings reveal vulnerabilities potentially exploitable for tackling breast tumors bearing missense TP53 mutations.

SUBMITTER: Tombari C

PROVIDER: S-EPMC10600207 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.

Tombari Camilla C Zannini Alessandro A Bertolio Rebecca R Pedretti Silvia S Audano Matteo M Triboli Luca L Cancila Valeria V Vacca Davide D Caputo Manuel M Donzelli Sara S Segatto Ilenia I Vodret Simone S Piazza Silvano S Rustighi Alessandra A Mantovani Fiamma F Belletti Barbara B Baldassarre Gustavo G Blandino Giovanni G Tripodo Claudio C Bicciato Silvio S Mitro Nico N Del Sal Giannino G

Nature communications 20231025 1

Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. Th ...[more]

PMID: 37880212

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Project description:Reducing the dependency on soybean meal (SBM) is necessary to improve the sustainability of the poultry industry. Moreover, the recommendations for minimum contents of dietary Gly+Ser require further research. Two parallel studies were executed to determine the effects of replacing SBM with crystalline amino acids (CAA) to meet the amino acid requirements and to determine whether a minimum content of Gly+Ser is necessary for broiler diets. In study 1, 1,860 one-day-old male chicks were fed a common starter phase diet (22.8% CP). During the grower-1, grower-2, and finisher phases, the control CP content was reduced (up to 2.1%) with the stepwise addition of CAA (treatments 1-5). Within each feeding phase, AME, standardized ileal digestible Lys, and the minimum Met, Thr, Val, Gly+Ser, Ile, Arg, and Trp to Lys ratios were similar. In study 2, 1,488 male chickens were used in a 2 × 2 factorial design with the Gly+Ser content and feed ingredients used as main factors. Performance was monitored during 41 d in both studies. Reduction in CP content linearly increased (P < 0.05) BW, ADG, and ADFI in the grower-1, grower-2, and finisher phases. When the overall FCR was adjusted considering the BW differences (FCRadj); FCRadj linearly decreased with the weighted average CP (WACP) content (P < 0.001). In the lowest CP treatment, estimated dietary N utilization efficiency was improved by 10%, and the overall N excretion was reduced by 16% compared with the control (P < 0.001). The overall SBM and soybean oil intakes were linearly reduced relative to WACP (-12.0 and -20.2% in control vs. treatment 5, respectively; P < 0.001). Formulating with a minimum Gly+Ser content in the starter phase improved the FCR (P < 0.05) only in the corn-SBM-based diet. In grower-1, increasing Gly+Ser content improved the FCR independent of the feed ingredients used (P < 0.05). Crystalline amino acids can be used to partially replace intact protein reducing the dependency on SBM. Young birds may not synthesize enough Gly endogenously and a minimum content should be provided in the early phases.

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Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.

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Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.

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