Erianin regulates programmed cell death ligand 1 expression and enhances cytotoxic T lymphocyte activity
Erianin regulates programmed cell death ligand 1 expression and enhances cytotoxic T lymphocyte activity
复制标题
毛兰素调节程序性细胞死亡配体 1 表达并增强细胞毒性 T 淋巴细胞活性
DOI：
10.1016/j.jep.2020.113598
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发表时间：
2021-03-18
影响因子：
5.4
通讯作者：
Jin, Xuejun
中科院分区：
文献类型：
--
作者：
Yang, Ao;Li, Ming Yue;Jin, Xuejun
民族药理学相关性：Dendrobium chrysotoxum Lindl是一种属于兰科的石斛属植物。D.早在世纪B，chrysotoxum Lindl是一种具有广泛临床应用的传统中药，包括滋补、收敛、镇痛和抗炎性质。C.毛兰素是毛兰药材质量控制的代表性指标成分。《中国药典》收载的金龟子？研究目的：阐明毛兰素的体内外抗肿瘤机制。材料与方法：采用体外HeLa细胞模型和体内宫颈癌移植瘤模型检测毛兰素的抗肿瘤活性。我们进行了MTT，Western blot，RT-PCR，同源模建，流式细胞术，免疫沉淀分析，研究相关的蛋白质，基因和途径毛兰素？的抗肿瘤活性。进行LysoTracker Red染色以检测溶酶体功能。分别进行Transwell、伤口愈合、管形成、集落形成和EdU标记测定以确定细胞增殖、迁移和侵袭能力。结果：毛兰素抑制PD-L1的表达，并诱导PD-L1的溶酶体降解。毛兰素抑制HIF-1？通过mTOR/p70 S6 K/4 EBP 1途径合成，并抑制RAS/Raf/MEK/MAPK-ERK途径。免疫沉淀实验表明毛兰素可降低RAS与HIF-1？的相互作用。使用T细胞和HeLa细胞的共培养系统的实验证实毛兰素恢复细胞毒性T淋巴细胞杀死肿瘤细胞的能力。毛兰素抑制PDL 1？介导的血管生成、增殖、侵袭和迁移。毛兰素的抗增殖作用的支持使用在体内异种transplantation experiments.Conclusions：总的来说，这些结果揭示了毛兰素以前未知的属性，并提供了一个新的基础，通过PD-L1提高免疫治疗对宫颈癌和其他恶性肿瘤的疗效。
Ethnopharmacological relevance: Dendrobium chrysotoxum Lindl is a cultivation of Dendrobium which belongs to the family of Orchidaceae. D. chrysotoxum Lindl is a traditional Chinese medicine with a wide range of clinical applications including tonic, astringent, analgesic and anti-inflammatory properties as early as the 28th century B. C. Erianin is a representative index component for the quality control of the D. chrysotoxum Lindl, which is included in the Pharmacopoeia of the People?s Republic of China (2020 version).Aim of the study: To clarify the anti-tumour mechanisms of erianin in vitro and in vivo. Materials and methods: We detected the anti-tumour activity of erianin using in vitro HeLa cell models and in vivo cervical cancer xenograft models. We performed MTT, western blot, RT-PCR, homology modeling, flow cytometry, and immunoprecipitation assays to study the proteins, genes, and pathways related to erianin?s antitumour activity. LysoTracker Red staining was performed to detect lysosome function. Transwell, wound healing, tube formation, colony formation and EdU labelling assays were performed to determine cell proliferation, migration and invasion abilities, respectively. Cytotoxic T lymphocytes ability was confirmed using HeLa/T-cell co-culture model.Results: Experimental data demonstrated that erianin inhibited PD-L1 expression and induced the lysosomal degradation of PD-L1. Erianin suppressed HIF-1? synthesis through mTOR/p70S6K/4EBP1 pathway, and inhibited RAS/Raf/MEK/MAPK-ERK pathway. Immunoprecipitation experiments demonstrated that erianin reduced the interaction between RAS and HIF-1?. Experiments using a co-cultivation system of T cells and HeLa cells confirmed that erianin restored cytotoxic T lymphocytes ability to kill tumour cells. Erianin inhibited PDL1?mediated angiogenesis, proliferation, invasion and migration. The anti-proliferative effects of erianin were supported using in vivo xenotransplantation experiments.Conclusions: Collectively, these results revealed previously unknown properties of erianin and provided a new basis for improving the efficacy of immunotherapy against cervical cancer and other malignant tumours through PD-L1.