Celastrol Elicits Antitumor Effects through Inducing Immunogenic Cell Death and Downregulating PD-L1 in ccRCC


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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.

About the authors

Hong-Fang Li

Laboratory of Stem Cell Regulation with Chinese Medicine and its Application, Department of Clinical Pharmacy, School of Pharmacy,, Hunan University of Chinese Medicine

Email: info@benthamscience.net

Neng Zhu

Department of Urology, The First Hospital of Hunan University of Chinese Medicine

Email: info@benthamscience.net

Jia-Jun Wu

Laboratory of Stem Cell Regulation with Chinese Medicine and its Application, Department of Clinical Pharmacy, School of Pharmacy,, Hunan University of Chinese Medicine

Email: info@benthamscience.net

Ya-Ning Shi

Science and Technology Innovation Center, Hunan University of Chinese Medicine,

Email: info@benthamscience.net

Jia Gu

Laboratory of Stem Cell Regulation with Chinese Medicine and its Application, Department of Clinical Pharmacy, School of Pharmacy,, Hunan University of Chinese Medicine

Email: info@benthamscience.net

Li Qin

Laboratory of Stem Cell Regulation with Chinese Medicine and its Application, Department of Clinical Pharmacy, School of Pharmacy,, Hunan University of Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

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