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.
Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410208, Hunan, China.
Curr Pharm Des. 2024;30(16):1265-1278. doi: 10.2174/0113816128288970240321073436.
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 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.
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).
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 . 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.
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.
靶向免疫原性细胞死亡（ICD）被认为是癌症治疗的一种很有前途的策略。然而，通常识别的 ICD 诱导剂会促进肿瘤细胞程序性死亡配体 1（PD-L1）的表达，从而帮助它们逃避免疫系统的识别和杀伤。因此，寻找新的 ICD 诱导剂以避免增强 PD-L1 的表达对于癌症治疗至关重要。从 Hook. F 中分离出的三萜 Celastrol（CeT）可诱导多种形式的细胞死亡以发挥抗癌作用，这使得 Celastrol 成为诱导 ICD 的有吸引力的候选药物。
本研究结合生物信息学分析和实验验证，探讨了 CeT 诱导 ICD 及其调节透明细胞肾细胞癌（ccRCC）中 PD-L1 表达的潜在机制。
结果表明，EGFR、IKBKB、PRKCQ 和 MAPK1 是 CeT 诱导 ICD 的关键靶标，只有 MAPK1 是 ccRCC 患者总生存期（OS）的独立预后因素。此外，CeT 触发自噬并上调 HMGB1 和 CRT 的表达，从而诱导 786-O 细胞发生 ICD。重要的是，CeT 可以通过激活自噬来下调 PD-L1 的表达。在分子水平上，CeT 通过抑制 MAPK1 表达来抑制 PD-L1。免疫方面，Celastrol 的核心靶点 MAPK1 与 ccRCC 中的 CD8+T 细胞和 CD4+T 细胞密切相关。
这些发现表明，CeT 不仅通过下调 MAPK1 表达诱导 ICD，还抑制 PD-L1，为 ccRCC 免疫治疗提供了一种有吸引力的策略。
