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定量蛋白组学揭示雷公藤红素抗卵巢癌的作用机制

Mechanisms of celastrol for ovarian cancer: based on quantitative proteomics
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摘要 目的探讨雷公藤红素对卵巢癌细胞的增殖和迁移能力的抑制作用及其分子机制。方法通过细胞增殖及迁移实验,明确雷公藤红素抗卵巢癌细胞增殖及迁移的能力;利用定量蛋白组学结合生物信息学分析差异表达蛋白,解析雷公藤红素对卵巢癌的作用机制;通过体外分子生物学技术,检测雷公藤红素对卵巢癌细胞EMT标志物(Cadherin)、细胞迁移关键蛋白(CD44与HMGB)的表达水平,以及对细胞活性氧(ROS)诱导水平的影响。结果雷公藤红素显著抑制SKOV3及OVCAR3细胞增殖及迁移的能力。通过蛋白组学研究发现,经过雷公藤红素处理后,共有396个DEPs被鉴定出来(126个上调,270个下调)。GO和KEGG通路富集分析均显示雷公藤红素多靶点的抗肿瘤活性与细胞迁移、炎症、缺氧等生物过程密切相关。雷公藤红素下调N-cadherin,上调E-cadherin的表达抑制EMT,抑制CD44与HMGB1、HMGB2的表达来抑制卵巢癌细胞伤口愈合。此外,雷公藤红素诱导ROS的产生。结论雷公藤红素具有多靶向抗卵巢癌活性,其可通过抑制EMT过程并诱导ROS的产生,抑制细胞迁移与增殖,发挥抗卵巢癌的作用。 Objective To explore the inhibitory effect of celastrol on proliferation and migration of ovarian cancer cells and the molecular mechanism.Methods The ability of celastrol to inhibit the proliferation and migration of ovarian cancer cells was confirmed by MTT and wound healing assays.Proteomics was performed to discriminate the differentially expressed proteins(DEPs)associated with the inhibitory effects of celastrol on ovarian cells.EMT markers(cadherin switch)and key proteins that regulated cell migration(CD44 and HMGB)in ovarian cancer cells were detected using Western blot.The effect of celastrol on reactive oxygen species(ROS)production in ovarian cancer cells was determined via immunofluorescence measurement.Results Celastrol significantly inhibited the proliferation and migration of SKOV3 and OVCAR3 cells.396 DEPs were identified in ovarian cells treated with celastrol(126 up-regulated and 270 down-regulated)based on proteomics.The analysis of both GO and KEGG pathways showed that the multi-target anti-tumor activity of celastrol was related to cell migration,inflammation and hypoxia.Celastrol inhibited EMT by down-regulating N-cadherin and up-regulating E-cadherin.Celastrol also retarded the healing of ovarian cancer cells by inhibiting the expressions CD44,HMGB1 and HMGB2.Conclusion Proteomics studies have found that celastrol has multi-targeted anti-ovarian cancer activities.Celastrol can inhibit the migration and proliferation of ovarian cancer cells by inhibiting the process of EMT and inducing the production of ROS.
作者 马启宏 史渊源 陈芳芳 吴康 卜子轩 卢天公 MA Qihong;SHI Yuanyuan;CHEN Fangfang;WU Kang;BU Zixuan;LU Tiangong(School of Life Sciences,Beijing University of Chinese Medicine,Beijing 100029,China;Shenzhen Research Institute,Beijing University of Chinese Medicine,Shenzhen Guangdong 518118,China)
出处 《中国药物警戒》 2023年第7期721-727,757,共8页 Chinese Journal of Pharmacovigilance
基金 国家自然科学基金资助项目(82104460) 北京中医药大学揭榜挂帅项目资助课题(2022-JYB-JBZR-023) 北京中医药大学纵向科研发展基金会项目(2170072120008)。
关键词 卵巢癌 雷公藤红素 定量蛋白组学 上皮间充质转化 迁移 ovarian cancer celastrol quantitative proteomics epithelial mesenchymal transformation migration
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