Celastrol Elicits Antitumor Effects through Inducing Immunogenic Cell Death and Downregulating PD-L1 in ccRCC.
Curr Pharm Des
; 30(16): 1265-1278, 2024.
Article
de En
| MEDLINE
| ID: mdl-38584553
ABSTRACT
BACKGROUND:
Targeting immunogenic cell death (ICD) is considered a promising therapeutic strategy for cancer. However, the commonly identified ICD inducers promote the expression of programmed cell death ligand 1 (PD-L1) in tumor cells, thus aiding them to evade the recognition and killing by the immune system. Therefore, the finding of novel ICD inducers to avoid enhanced PD-L1 expression is of vital significance for cancer therapy. Celastrol (CeT), a triterpene isolated from Tripterygium wilfordii Hook. F induces various forms of cell death to exert anti-cancer effects, which may make celastrol an attractive candidate as an inducer of ICD.METHODS:
In the present study, bioinformatics analysis was combined with experimental validation to explore the underlying mechanism by which CeT induces ICD and regulates PD-L1 expression in clear cell renal cell carcinoma (ccRCC).RESULTS:
The results showed that EGFR, IKBKB, PRKCQ and MAPK1 were the crucial targets for CeT-induced ICD, and only MAPK1 was an independent prognostic factor for the overall survival (OS) of ccRCC patients. In addition, CeT triggered autophagy and up-regulated the expressions of HMGB1 and CRT to induce ICD in 786-O cells in vitro. Importantly, CeT can down-regulate PD-L1 expression through activating autophagy. At the molecular level, CeT suppressed PD-L1 via the inhibition of MAPK1 expression. Immunologically, the core target of celastrol, MAPK1, was tightly correlated with CD8+ T cells and CD4+ T cells in ccRCC.CONCLUSION:
These findings indicate that CeT not only induces ICD but also suppresses PD-L1 by down-regulating MAPK1 expression, which will provide an attractive strategy for ccRCC immunotherapy.Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Néphrocarcinome
/
Régulation négative
/
Triterpènes pentacycliques
/
Antigène CD274
/
Tumeurs du rein
Limites:
Humans
Langue:
En
Journal:
Curr Pharm Des
Sujet du journal:
FARMACIA
Année:
2024
Type de document:
Article
Pays d'affiliation:
Chine