顺铂联合半夏科脂溶性提取物诱导宫颈癌免疫原性细胞死亡。
Combining cisplatin with Pinellia pedatisecta Schott lipid-soluble extract induces tumor immunogenic cell death in cervical cancer.
机构信息
Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China.
Department of Anaesthesiology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China.
出版信息
Phytomedicine. 2024 Jun;128:155504. doi: 10.1016/j.phymed.2024.155504. Epub 2024 Mar 3.
BACKGROUND
Pinellia pedatisecta Schott extract (PE) is extracted from Pinellia pedatisecta Schott (PPS), a traditional Chinese medicinal plant with the potential for direct anticancer effects or eliciting an anti-tumor response by activating the immune system.
PURPOSE
To explore PE's ability and mechanism to reconstruct cisplatin's immunogenicity.
METHODS
Cervical cancer cells were treated with cisplatin (CDDP) and/or PE. The exposure of calreticulin (CRT) on cell membrane was investigated by flow cytometry. The extracellular of ATP and HMGB1 was investigated by Western blot analysis, immunofluorescence and ELISA assay. Changes in immune profiles were using flow cytometry in vaccination and anti-tumor assays in vivo. Lastly, the mechanism of PE influenced the ROS/ERS pathway was examined by ROS assay kit, flow cytometry and Western blotting.
RESULTS
PE treatment induced translocation of CRT from the endoplasmic reticulum to the cell membrane of tumor cells, concomitantly triggering immunogenic cell death (ICD). In terms of mechanisms, endoplasmic reticulum (ER) stress relievers could impede the ability of PE to induce immunogenicity. This indicates that PE is activated by ER stress, leading to subsequent induction of ICD. Upon analyzing RNA-seq data, it was observed that PE primarily induces programmed cell death in tumors by impeding upstream antioxidant mechanisms. Additionally, it transforms dying tumor cells into vaccines, activating a series of immune responses.
CONCLUSIONS
This study observed for the first time that PE-induced CRT exposure on the membrane of cervical cancer cells compensates for the defect of nonimmunogenic cell death inducer CDDP thereby stimulating potent ICD. This ability restores the immunogenicity of CDDP through ER stress induced by the ROS signal. ROS played a role in PE's ability to induce ICD, leading to increased expression of ER stress-related proteins, including ATF3 and IRE-1α. PE exerted anti-cancer effects by increasing the ROS levels, and ROS/ERS signaling may be a potential avenue for cervical cancer treatment. Hence, the synergistic use of PE and CDDP holds potential for enhancing immunochemotherapy in cancer treatment.
背景
半夏提取物（PE）是从半夏（PPS）中提取的，半夏是一种具有直接抗癌作用或通过激活免疫系统引起抗肿瘤反应潜力的传统中药。
目的
探讨 PE 重建顺铂免疫原性的能力和机制。
方法
用顺铂（CDDP）和/或 PE 处理宫颈癌细胞。通过流式细胞术研究细胞膜上钙网蛋白（CRT）的暴露情况。通过 Western blot 分析、免疫荧光和 ELISA 测定研究细胞外 ATP 和高迁移率族蛋白 B1（HMGB1）的变化。用流式细胞术在体内疫苗接种和抗肿瘤实验中检测免疫谱的变化。最后，用 ROS 测定试剂盒、流式细胞术和 Western blot 检测 PE 影响 ROS/ERS 途径的机制。
结果
PE 处理诱导 CRT 从内质网易位到肿瘤细胞的细胞膜，同时触发免疫原性细胞死亡（ICD）。在机制方面，内质网（ER）应激缓解剂可阻碍 PE 诱导免疫原性的能力。这表明 PE 通过 ER 应激激活，随后诱导 ICD。通过分析 RNA-seq 数据，观察到 PE 主要通过抑制上游抗氧化机制诱导肿瘤细胞程序性死亡。此外，它将垂死的肿瘤细胞转化为疫苗，激活一系列免疫反应。
结论
本研究首次观察到，PE 诱导 CRT 暴露于宫颈癌细胞膜上，弥补了非免疫原性细胞死亡诱导剂 CDDP 的缺陷，从而刺激强烈的 ICD。这种能力通过 ROS 信号诱导的 ER 应激恢复 CDDP 的免疫原性。ROS 在 PE 诱导 ICD 的能力中发挥作用，导致 ER 应激相关蛋白（包括 ATF3 和 IRE-1α）的表达增加。PE 通过增加 ROS 水平发挥抗癌作用，ROS/ERS 信号可能是治疗宫颈癌的潜在途径。因此，PE 和 CDDP 的协同使用有可能增强癌症治疗中的免疫化疗。
Zotero 插件