定量蛋白组学揭示雷公藤红素抗卵巢癌的作用机制

doi:10.19803/j.1672-8629.20230197

中国药物警戒 ›› 2023, Vol. 20 ›› Issue (7): 721-727.
DOI: 10.19803/j.1672-8629.20230197

• 中药及其活性成分抗肿瘤作用研究专栏 • 上一篇下一篇

定量蛋白组学揭示雷公藤红素抗卵巢癌的作用机制

马启宏¹, 史渊源^1,2, 陈芳芳¹, 吴康¹, 卜子轩¹, 卢天公^1,*

¹北京中医药大学生命科学学院,北京 100029;
²深圳北京中医药大学研究院,广东深圳 518118

收稿日期:2023-04-03 出版日期:2023-07-15 发布日期:2023-07-14
通讯作者: ^*卢天公,女,博士,副教授,中西医结合抗肿瘤药效及药理学研究。E-mail：lutiangong@163.com
作者简介:马启宏,男,在读硕士,中药抗肿瘤药理研究。
基金资助:
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）

Mechanisms of celastrol for ovarian cancer: based on quantitative proteomics

MA Qihong¹, SHI Yuanyuan^1,2, CHEN Fangfang¹, WU Kang¹, BU Zixuan¹, LU Tiangong^1,*

¹School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China;
²Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen Guangdong 518118, China

Received:2023-04-03 Online:2023-07-15 Published:2023-07-14

摘要/Abstract

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。

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

Abstract: 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.

Key words: ovarian cancer, celastrol, quantitative proteomics, epithelial mesenchymal transformation, migration

中图分类号:

马启宏, 史渊源, 陈芳芳, 吴康, 卜子轩, 卢天公. 定量蛋白组学揭示雷公藤红素抗卵巢癌的作用机制[J]. 中国药物警戒, 2023, 20(7): 721-727.

MA Qihong, SHI Yuanyuan, CHEN Fangfang, WU Kang, BU Zixuan, LU Tiangong. Mechanisms of celastrol for ovarian cancer: based on quantitative proteomics[J]. Chinese Journal of Pharmacovigilance, 2023, 20(7): 721-727.

参考文献

[1] SUNG H, FERLAY J, SIEGEL RL, et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[2] YANG JX,SHEN J,WU LY,et al.Discussion of BRCA gene testing in epithelial ovarian cancer in China[J]. Chinese Journal of Obstetrics and Gynecology(中华妇产科杂志), 2017,52(1): 8-10.
[3] GUO LH, YU M, WU XH.Progress in diagnosis and treatment of gynecological tumors in 2022[J]. China Oncology(中国癌症杂志), 2023, 33(1): 14-24.
[4] KLYMENKO Y, KIM O, STACK MS.Complex determinants of epithelial: mesenchymal phenotypic plasticity in ovarian cancer[J]. Cancers (Basel), 2017, 9(8): 104.
[5] XU YY, JIANG SM .One case of hepatic dysfunction induced by olaparib tablets[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2019, 16(12): 762-764.
[6] JIANG HX, WU QS, LIU L, et al.Research progress of tripterygium wilfordii triterpenoids and their pharmacological activities[J]. Chinese Traditional Patent Medicine(中成药), 2022, 44(4): 1223-1231.
[7] CORSON TW, CREWS CM.Molecular understanding and modern application of traditional medicines: triumphs and trials[J]. Cell, 2007, 130(5): 769-774.
[8] LI XL, ZHU GB, ZHOU WY.Disruption of mTOR protein stability by celastrol in breast cancer[J]. Chinese Journal of Pharmacology and Toxicology(中国药理学与毒理学杂志), 2016, 30(10): 1059.
[9] GONG JJ, HU YS.Effects of celastrol on proliferation, apoptosis, and migration of glioma U87 cells[J]. Chinese Traditional and Herbal Drugs(中草药), 2017, 48(24): 5194-5199.
[10] LIU X, ZHAO P, WANG X, et al.Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells[J]. J Exp Clin Cancer Res, 2019, 38(1): 184.
[11] CHANG W, HE W, LI PP, et al.Protective effects of Celastrol on diethylnitrosamine-induced hepatocellular carcinoma in rats and its mechanisms[J]. Eur J Pharmacol, 2016, 784: 173-180.
[12] CHEN X, ZHAO Y, LUO W, et al.Celastrol induces ROS-mediated apoptosis via directly targeting peroxiredoxin-2 in gastric cancer cells[J]. Theranostics, 2020, 10(22): 10290-10308.
[13] GUO D, ZHANG W, YANG H, et al.Celastrol induces necroptosis and ameliorates inflammation via targeting biglycan in human gastric carcinoma[J]. Int J Mol Sci, 2019, 20(22): 5716.
[14] KANNAIYAN R, MANU KA, CHEN L, et al.Celastrol inhibits tumor cell proliferation and promotes apoptosis through the activation of c-Jun N-terminal kinase and suppression of PI3 K/Akt signaling pathways[J]. Apoptosis, 2011, 16(10): 1028-1041.
[15] SHI J, LI J, XU Z, et al.Celastrol: a review of useful strategies overcoming its limitation in anticancer application[J]. Front Pharmacol, 2020, 11: 558741.
[16] SERRANO-GOMEZ SJ, MAZIVEYI M, ALAHARI SK.Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications[J]. Mol Cancer, 2016, 15: 18.
[17] YANG J, ANTIN P, BERX G, et al.Guidelines and definitions for research on epithelial-mesenchymal transition[J]. Nat Rev Mol Cell Biol, 2020, 21(6): 341-352.
[18] SMITH AG, MACLEOD KF.Autophagy, cancer stem cells and drug resistance[J]. J Pathol, 2019, 247(5): 708-718.
[19] BARREIRO-ALONSO A, LAMAS-MACEIRAS M, RODRIGUEZ-BELMONTE E, et al.High mobility group b proteins, their partners, and other redox sensors in ovarian and prostate cancer[J]. Oxid Med Cell Longev, 2016, 2016: 5845061.
[20] LEE SY, JEONG EK, JU MK, et al.Induction of metastasis, cancer stem cell phenotype,and oncogenic metabolism in cancer cells by ionizing radiation[J]. Mol Cancer, 2017, 16(1): 10.
[21] CHEUNG EC, VOUSDEN KH.The role of ROS in tumour development and progression[J]. Nat Rev Cancer, 2022, 22(5): 280-297.
[22] XU S, FAN R, WANG L, et al.Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition[J]. J Enzyme Inhib Med Chem, 2022, 37(1): 236-251.
[23] METSELAAR DS, MEEL MH, BENEDICT B, et al.Celastrol-induced degradation of FANCD2 sensitizes pediatric high-grade gliomas to the DNA-crosslinking agent carboplatin[J]. EBioMedicine, 2019, 50: 81-92.
[24] NIETO MA, HUANG RY, JACKSON RA, et al.Emt: 2016[J]. Cell, 2016, 166(1): 21-45.
[25] LENGYEL E.Ovarian cancer development and metastasis[J]. Am J Pathol, 2010, 177(3): 1053-1064.
[26] KLYMENKO Y, JOHNSON J, BOS B, et al.Heterogeneous cadherin expression and multicellular aggregate dynamics in ovarian cancer dissemination[J]. Neoplasia, 2017, 19(7): 549-563.
[27] KIELBIK M, SZULC-KIELBIK I, KLINK M.E-cadherin expression in relation to clinicopathological parameters and survival of patients with epithelial ovarian cancer[J]. Int J Mol Sci, 2022, 23(22): 14383.
[28] ZHANG CJ, ZHU N, LONG J, et al.Celastrol induces lipophagy via the LXRα/ABCA1 pathway in clear cell renal cell carcinoma[J]. Acta Pharmacol Sin, 2021, 42(9): 1472-1485.
[29] HANAHAN D, WEINBERG RA.Hallmarks of cancer: the next generation[J]. Cell, 2011,144(5): 646-674.
[30] SRINIVAS US, TAN BWQ, VELLAYAPPAN BA, et al.ROS and the DNA damage response in cancer[J]. Redox Biol, 2019, 25: 101084.
[31] XU H, ZHAO H, DING C, et al.Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin[J]. Signal Transduct Target Ther, 2023, 8(1): 51.

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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