Increased ATF2 expression predicts poor prognosis and inhibits sorafenib-induced ferroptosis in gastric cancer.
Redox Biol
; 59: 102564, 2023 02.
Article
em En
| MEDLINE
| ID: mdl-36473315
ABSTRACT
Sorafenib, a tyrosine kinase inhibitor, has an important antitumor effect as a ferroptosis inducer in multiple cancers, including gastric cancer (GC). However, the status of sorafenib as a ferroptosis inducer has recently been questioned. There is very limited information about the relationship between ferroptosis and ATF2, and the role of ATF2 in sorafenib-induced ferroptosis has not been studied. In this study, we investigated the role and underlying molecular mechanisms of ATF2 in sorafenib-induced ferroptosis in GC. We found that ATF2 was significantly upregulated in GC tissues and predicted a poor clinical prognosis. Silencing ATF2 significantly inhibited the malignant phenotype of GC cells. In addition, we observed that ATF2 was activated during sorafenib-induced ferroptosis in GC cells. ATF2 knockdown promoted sorafenib-induced ferroptosis, while ATF2 overexpression showed the opposite results in GC cells. Using ChIP-Seq and RNA-Seq, we identified HSPH1 as a target of ATF2 and further validated it by ChIPâqPCR analysis. HSPH1 can interact with SLC7A11 (cystine/glutamate transporter) and increase its protein stability. Importantly, knockdown of HSPH1 partly reversed the effects caused by ATF2 overexpression on sorafenib-induced ferroptosis in GC cells. In addition, the results from the tumor xenograft model showed that ATF2 knockdown can effectively enhance sorafenib sensitivity in vivo. Collectively, our study reveals a novel mechanism by which sorafenib induces ferroptosis in GC.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
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Ferroptose
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Redox Biol
Ano de publicação:
2023
Tipo de documento:
Article