Ginsenoside Rg3 activates the immune function of CD8+ T cells via circFOXP1-miR-4477a-PD-L1 axis to induce ferroptosis in gallbladder cancer.

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2024-10-28 DOI:10.1007/s12272-024-01516-y
Zhipeng Ye, Jianfeng Ding, Jie Huang, Zhao Hu, Fa Jin, Keren Wu
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Abstract

Gallbladder cancer (GBC) is the most common and leading cause of cancer-associated mortality among biliary tract carcinomas worldwide and there is no specific drug for treatment. Activation of CD8+ T cell immune activity is one of the strategies to improve GBC treatment. This study is aimed to investigate the role of Ginsenoside Rg3 on CD8+ T cell activation and pathogenesis of GBC. In GBC cells, Rg3 administration led to the significant reduction of circFOXP1 and PD-L1 as measured by Quantitative real-time polymerase chain reaction (RT-qPCR) and Western blotting. Mechanistically, circFOXP1 acted as the sponge of miR-4477a to regulate PD-L1 expression as demonstrated by RNA pull-down assay and dual luciferase reporter assay. Rg3 treatment enhanced the activity of CD8+ T cells by inhibiting the circFOXP1/miR-4477a/PD-L1 signaling axis. Besides, Rg3 administration induced lipid oxidation and ROS reduction as detected by Flow cytometry, resulting in ferroptosis via the inactivation of circFOXP1/miR-4477a/PD-L1 axis. Ferroptosis inhibitor Fer-1 administration could reverse the beneficial effects caused by Rg3 treatment while ferroptosis inducer Erastin treatment enhanced the effects. Moreover, Rg3 gavage alleviated tumor growth and elevated ferroptosis and apoptosis in tumor tissues, which were prevented by PD-L1 overexpression. Furthermore, Rg3 was demonstrated to activate the function of CD8+ T cells via regulating the circFOXP1-miR-4477a-PD-L1 signaling axis in vivo. Rg3 inactivated the circFOXP1-miR-4477a-PD-L1 signaling axis to activate the immune function of CD8+ T cells, thereby inducing ferroptosis and apoptosis in GBC cells. This research recognizes the mechanism of Rg3-mediated anti-cancer effect and offers evidence for the potentiality of Rg3 in clinical application for GBC therapy.

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人参皂苷Rg3通过circFOXP1-miR-4477a-PD-L1轴激活CD8+T细胞的免疫功能,诱导胆囊癌的铁变态反应。
胆囊癌(GBC)是全球最常见的胆道癌,也是导致癌症相关死亡的主要原因,目前尚无特效药物可用于治疗。激活 CD8+ T 细胞免疫活性是改善 GBC 治疗的策略之一。本研究旨在探讨人参皂苷 Rg3 对 CD8+ T 细胞活化和 GBC 发病机制的作用。通过定量实时聚合酶链式反应(RT-qPCR)和 Western 印迹法测定,在 GBC 细胞中服用 Rg3 能显著降低 circFOXP1 和 PD-L1。从机理上讲,circFOXP1是miR-4477a调控PD-L1表达的海绵,这一点已通过RNA牵引实验和双荧光素酶报告实验得到证实。通过抑制 circFOXP1/miR-4477a/PD-L1 信号轴,Rg3 治疗增强了 CD8+ T 细胞的活性。此外,流式细胞仪检测到,Rg3能诱导脂质氧化和ROS减少,从而通过抑制circFOXP1/miR-4477a/PD-L1轴导致铁变态反应。给予铁变态反应抑制剂 Fer-1 可以逆转 Rg3 治疗所产生的有益影响,而给予铁变态反应诱导剂 Erastin 则可以增强其效果。此外,灌胃 Rg3 可减轻肿瘤生长,促进肿瘤组织中的铁凋亡和细胞凋亡,而 PD-L1 过表达可阻止这些作用。此外,Rg3 还能通过调节 circFOXP1-miR-4477a-PD-L1 信号轴激活体内 CD8+ T 细胞的功能。Rg3使circFOXP1-miR-4477a-PD-L1信号轴失活,激活了CD8+ T细胞的免疫功能,从而诱导了GBC细胞的铁变态反应和凋亡。这项研究揭示了Rg3介导的抗癌作用机制,并为Rg3在GBC治疗中的临床应用潜力提供了证据。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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