GPX4 transcriptionally promotes liver cancer metastasis via GRHL3/PTEN/PI3K/AKT axis.
Transl Res
; 271: 79-92, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-38797432
ABSTRACT
Hepatocellular carcinoma (HCC) is among the most fatal types of malignancy, with a high prevalence of relapse and limited treatment options. As a critical regulator of ferroptosis and redox homeostasis, glutathione peroxidase 4 (GPX4) is commonly upregulated in HCC and is hypothesized to facilitate cancer metastasis, but this has not been fully explored in HCC. Here, we report that up-regulated GPX4 expression in HCC is strongly associated with tumor metastasis. FACS-based in vivo and in vitro analysis revealed that a cell subpopulation featuring lower cellular reactive oxygen species levels and ferroptosis resistance were involved in GPX4-mediated HCC metastasis. Mechanistically, GPX4 overexpressed in HCC tumor cells was enriched in the nucleus and transcriptionally silenced GRHL3 expression, thereby activating PTEN/PI3K/AKT signaling and promoting HCC metastasis. Functional studies demonstrated that GPX4 amino acids 110-145 are a binding site that interacts with the GRHL3 promoter. As AKT is a downstream target of GPX4, we combined the AKT inhibitor, AKT-IN3, with lenvatinib to effectively inhibit HCC tumor cell metastasis. Overall, these results indicate that the GPX4/GRHL3/PTEN/PI3K/AKT axis controls HCC cell metastasis and lenvatinib combined with AKT-IN3 represents a potential therapeutic strategy for patients with metastatic HCC.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Transducción de Señal
/
Carcinoma Hepatocelular
/
Fosfatidilinositol 3-Quinasas
/
Proteínas de Unión al ADN
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Fosfohidrolasa PTEN
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Proteínas Proto-Oncogénicas c-akt
/
Fosfolípido Hidroperóxido Glutatión Peroxidasa
/
Neoplasias Hepáticas
/
Metástasis de la Neoplasia
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Transl Res
Asunto de la revista:
MEDICINA
/
TECNICAS E PROCEDIMENTOS DE LABORATORIO
Año:
2024
Tipo del documento:
Article
País de afiliación:
China