Title:Celastrol Elicits Antitumor Effects through Inducing Immunogenic Cell Death
and Downregulating PD-L1 in ccRCC
Volume: 30
Issue: 16
Author(s): Hong-Fang Li, Neng Zhu, Jia-Jun Wu, Ya-Ning Shi, Jia Gu and Li Qin*
Affiliation:
- Laboratory of Stem Cell Regulation with Chinese Medicine and its Application, Department of Clinical Pharmacy, School of Pharmacy,
Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Hunan Provincial Key Laboratory of Vascular Biology and Translational
Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
- Hunan Province Engineering Research
Center of Bioactive Substance Discovery of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha
410208, Hunan, China
Keywords:
Immunogenic cell death, clear cell renal cell carcinoma, celastrol, PD-L1, MAPK1, overall survival.
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.
