Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 10 2023
25 10 2023
Historique:
received:
04
08
2023
accepted:
11
10
2023
medline:
27
10
2023
pubmed:
26
10
2023
entrez:
25
10
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37880212
doi: 10.1038/s41467-023-42458-1
pii: 10.1038/s41467-023-42458-1
pmc: PMC10600207
doi:
Substances chimiques
Amino Acids
0
Amino Acids, Essential
0
Glycine
TE7660XO1C
Large Neutral Amino Acid-Transporter 1
0
Serine
452VLY9402
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6777Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. Springer Nature Limited.
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