摘要： 目的 探讨植物源性生物活性化合物玫瑰树碱对胰腺癌细胞的作用及其机制，为开发治疗胰腺癌的潜在天然抗癌药物提供理论基础。方法 评估玫瑰树碱对胰腺癌PANC-1细胞增殖和转移能力的影响，镜下观察焦亡相关细胞形态学特征，检测细胞内活性氧（ROS）含量的变化，研究玫瑰树碱的作用机制。Western blotting检测焦亡和线粒体代谢相关蛋白表达的变化。通过生物信息学方法分析焦亡相关蛋白对预后的影响，构建预后模型，分析焦亡相关基因与T细胞免疫招募的相关性。结果 玫瑰树碱能抑制PANC-1细胞的存活率和转移能力。玫瑰树碱处理后，PANC-1细胞明显涨大、变圆并发生破裂，细胞内ROS含量升高。焦亡相关蛋白caspase 3、caspase 4、gasdermin D和线粒体代谢相关蛋白TMEM70的表达均有不同程度上调。纳入IL-6、AIM2、NLRP1、caspase 4、IL-18、caspase 3基因表达的数据，并结合肿瘤的T、N分期建立胰腺癌生存预后模型。进一步结合生物信息学分析胰腺癌焦亡相关基因的表达，发现IL-6、AIM2、NRLP1可能参与T细胞招募。结论 玫瑰树碱能抑制胰腺癌PANC-1细胞的增殖和转移能力，使其产生焦亡后的形态学特征。同时，玫瑰树碱能够诱导PANC-1细胞发生焦亡，并可能引起炎症和免疫反应，从而增强其抗肿瘤效应。此外，玫瑰树碱可能通过干扰线粒体代谢、上调ROS、诱导焦亡，发挥对胰腺癌细胞的杀伤作用，可能提高其对化疗和免疫治疗等方法的敏感性。

玫瑰树碱诱导胰腺癌细胞焦亡的机制

曹丹^1,2, 陈星², 汤晓燕³, 张宇华², 邓尚贵¹

1. 浙江海洋大学食品与药学学院食品系, 浙江 舟山 316022;
2. 浙江省肿瘤医院肝胆胰外科, 杭州 310022;
3. 杭州医学院临床医学院临床医学系, 杭州 310059

收稿日期:2023-05-29出版日期:2023-11-30发布日期:2023-11-07
通讯作者:邓尚贵E-mail:dengshanggui@163.com
作者简介:曹丹(1992-),女,硕士研究生.
基金资助:浙江省基础公益研究计划（LQ23H160010）；浙江省中医药管理局项目（2017zkl005）


关键词: 玫瑰树碱, 胰腺癌, 焦亡, 生物信息学, 活性氧
Abstract: Objective To investigate the effect and mechanism of ellipticine, a plant-derived bioactive compound, on pancreatic cancer cells to provide a theoretical basis for the development of potential natural anticancer drugs for the treatment of pancreatic ductal adenocarcinoma (PDAC). Methods The effects of ellipticine on the proliferation and metastasis of PANC-1 cells were evaluated. The morphological characteristics of pyroptosis-related cells and the level of reactive oxygen species (ROS) in PANC-1 cells were observed microscopically to determine the mechanism of ellipticine. Western blotting was used to detect changes in the expression of proteins related to pyroptosis and mitochondrial metabolism. The effect of pyroptosis-related gene expression on prognosis was analyzed by bioinformatics. Results The survival rate and metastatic ability of PANC-1 cells were inhibited by ellipticine. After treatment with ellipticine, PANC-1 cells were significantly enlarged, ruptured, and exhibited increased ROS levels. The expression of caspase 3, caspase 4, gasdermin D, and TMEM70 proteins was upregulated. The expression data of IL-6, AIM2, NLRP1, caspase 4, IL-18, and caspase 3 genes were selected and combined with the T and N stages to establish a prognosis model of PDAC. Conclusion Ellipticine inhibits proliferation and metastasis in PANC-1 cells and induces the morphological characteristics of pyroptosis. At the same time, ellipticine may induce pyroptosis in PANC-1 cells, which may cause inflammatory and immune responses, enhancing its anti-tumor effect. Ellipticine is potentially an antitumor drug that interferes with mitochondrial metabolism, upregulates ROS, and induces pyroptosis. Furthermore, ellipticine may improve sensitivity to chemotherapy and immunotherapy in PDAC.
Key words: ellipticine, pancreatic ductal adenocarcinoma, pyroptosis, bioinformatics, reactive oxygen species
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