p53 suppresses lipid droplet-fueled tumorigenesis through phosphatidylcholine.
J Clin Invest
; 134(4)2024 Jan 09.
Article
em En
| MEDLINE
| ID: mdl-38194288
ABSTRACT
Choline deficiency causes disorders including hepatic abnormalities and is associated with an increased risk of multiple types of cancer. Here, by choline-free diet-associated RNA-Seq analyses, we found that the tumor suppressor p53 drives the Kennedy pathway via PCYT1B to control the growth of lipid droplets (LDs) and their fueling role in tumorigenesis. Mechanistically, through upregulation of PCYT1B, p53 channeled depleted choline stores to phosphatidylcholine (PC) biosynthesis during choline starvation, thus preventing LD coalescence. Cells lacking p53 failed to complete this response to choline depletion, leading to hepatic steatosis and tumorigenesis, and these effects could be reversed by enforcement of PCYT1B expression or restoration of PC abundance. Furthermore, loss of p53 or defects in the Kennedy pathway increased surface localization of hormone-sensitive lipase on LDs to release specific fatty acids that fueled tumor cells in vivo and in vitro. Thus, p53 loss leads to dysregulation of choline metabolism and LD growth and couples perturbed LD homeostasis to tumorigenesis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfatidilcolinas
/
Gotículas Lipídicas
Limite:
Humans
Idioma:
En
Revista:
J Clin Invest
/
J. clin. invest
/
Journal of clinical investigation
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China