SLC13A3 is a major effector downstream of activated ß-catenin in liver cancer pathogenesis.
Nat Commun
; 15(1): 7522, 2024 Aug 30.
Article
en En
| MEDLINE
| ID: mdl-39215042
ABSTRACT
Activated Wnt/ß-catenin pathway is a key genetic event in liver cancer development. Solute carrier (SLC) transporters are promising drug targets. Here, we identify SLC13A3 as a drug-targetable effector downstream of ß-catenin in liver cancer. SLC13A3 expression is elevated in human liver cancer samples with gain of function (GOF) mutant CTNNB1, the gene encoding ß-catenin. Activation of ß-catenin up-regulates SLC13A3, leading to intracellular accumulation of endogenous SLC13A3 substrates. SLC13A3 is identified as a low-affinity transporter for glutathione (GSH). Silencing of SLC13A3 downregulates the leucine transporter SLC7A5 via c-MYC signaling, leading to leucine depletion and mTOR inactivation. Furthermore, silencing of SLC13A3 depletes GSH and induces autophagic ferroptosis in ß-catenin-activated liver cancer cells. Importantly, both genetic inhibition of SLC13A3 and a small molecule SLC13A3 inhibitor suppress ß-catenin-driven hepatocarcinogenesis in mice. Altogether, our study suggests that SLC13A3 could be a promising therapeutic target for treating human liver cancers with GOF CTNNB1 mutations.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Beta Catenina
/
Neoplasias Hepáticas
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Nat Commun
/
Nature communications
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China