基于网络药理学和体外研究探讨木犀草素抑制食管鳞状细胞癌的分子机制

doi:10.19803/j.1672-8629.20220744

中国药物警戒 ›› 2023, Vol. 20 ›› Issue (9): 992-1001.
DOI: 10.19803/j.1672-8629.20220744

基于网络药理学和体外研究探讨木犀草素抑制食管鳞状细胞癌的分子机制

杨珍珍^1,3, 常成², 高娜^1,3, 张晓林¹, 宋银森¹, 刘颖¹, 范天黎^3,*

¹河南中医药大学第五临床医学院,郑州人民医院,河南郑州 450003;
²郑州城建职业学院,河南郑州 451200;
³郑州大学基础医学院,河南郑州 450001

收稿日期:2022-12-30 出版日期:2023-09-15 发布日期:2023-09-14
通讯作者: ^*范天黎,女,博士,教授,肿瘤药理。E-mail: fantianli@zzu.edu.cn
作者简介:杨珍珍,女,硕士,主管药师,肿瘤药理。
基金资助:
河南省自然科学基金资助项目（212300410393）; 河南省医学科技攻关计划联合共建项目（LHGJ20210696）

Molecular mechanism of luteolin for inhibiting esophageal squamous cell carcinoma based on network pharmacology and in vitro studies

YANG Zhenzhen^1,3, CHANG Cheng², GAO Na^1,3, ZHANG Xiaolin¹, SONG Yinsen¹, LIU Ying¹, FAN Tianli^3,*

¹The Fifth Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou People's Hospital, Zhengzhou Henan 450003, China;
²Zhengzhou Urban Construction Vocational College, Zhengzhou Henan 451200, China;
³School of Basic Medical Sciences, Zhengzhou University, Zhengzhou Henan 450001, China

Received:2022-12-30 Online:2023-09-15 Published:2023-09-14

摘要/Abstract

摘要： 目的采用网络药理学和体外研究探讨木犀草素（luteolin）抑制食管鳞状细胞癌（esophageal squamous cell carcinoma, ESCC）的分子机制。方法通过构建活性成分和疾病维恩图（Venn图）确定木犀草素和ESCC共同靶点,String数据库将共同靶点进行可视化,建立蛋白互作网络（PPI）。使用Cytoscape 3.9.1内置插件对Hub基因筛选,并运用R语言进行基因本体（GO）生物过程富集分析及KEGG通路分析。体外试验观察木犀草素对ESCC细胞系（TE-13和KYSE-510）的抑制作用,采用分子对接验证木犀草素和部分Hub基因的结合活性。结果共收集到木犀草素与ESCC共同靶点69个,并筛选出以AKT1、ESR1和SRC为代表的Hub靶基因。靶点主要涉及细胞氧化应激、蛋白质修饰等生物学功能和活性氧、炎症、细胞外基质等信号通路。其中选择PI3K-Akt信号通路验证网络药理分析结果的合理性。体外研究表明,木犀草素可阻止TE-13和KYSE-510细胞增殖、迁移和侵袭的能力,并抑制了FAK-SRC-PI3K-Akt通路中磷酸化蛋白的表达。此外,分子对接结果表明,木犀草素对FAK、SRC、Akt蛋白表现出良好的亲和力。结论木犀草素对ESCC的抑制性表现出多靶点多通路的特征,其阻碍了ESCC细胞增殖、迁移和侵袭,这可能与抑制FAK-SRC-PI3K-Akt通路有关。

关键词: 木犀草素, 食管鳞状细胞癌, 网络药理学, 分子对接, 信号通路, 作用机制

Abstract: Objective To investigate the molecular mechanism by which luteolin inhibits esophageal squamous cell carcinoma (ESCC) based on network pharmacology and in vitro studies. Methods The common targets of luteolin and ESCC were identified by constructing Venn diagrams of active ingredients and diseases. The common targets were visualized via the String database before a protein-protein interaction network (PPI) was established. The Hub genes were screened using the plug-in of Cytoscape 3.9.1. Gene Ontology (GO) enrichment analysis and KEGG pathway analysis were performed using the R programming language. The inhibitory effect of luteolin on ESCC cell lines (TE-13 and KYSE-510) was observed in vitro, and the binding activity of luteolin and Hub genes was verified by molecular docking. Results A total of 69 common targets of luteolin and ESCC were collected, and Hub target genes represented by AKT1, ESR1 and SRC were screened. The targets involved not only such biological functions as cellular oxidative stress and protein modification, but such signaling pathways as reactive oxygen species, inflammation, and extracellular matrix. The PI3K-Akt signaling was selected to verify the rationality of the results of the network pharmacology analysis. In vitro studies showed that luteolin inhibited the ability of TE-13 and KYSE-510 cells to proliferate, migrate, and invade, and reduced the expressions of phosphorylated proteins in the FAK-SRC-PI3K-Akt pathway. In addition, the results of molecular docking showed that luteolin showed good affinity for FAK, SRC and Akt. Conclusion The inhibition of ESCC by luteolin is characterized by multiple targets and multiple pathways, which may be related to the inhibition of the FAK-SRC-PI3K-Akt pathway.

Key words: luteolin, esophageal squamous cell carcinoma, network pharmacology, molecular docking, signaling pathway, mechanism of action

中图分类号:

R994.11
R285

杨珍珍, 常成, 高娜, 张晓林, 宋银森, 刘颖, 范天黎. 基于网络药理学和体外研究探讨木犀草素抑制食管鳞状细胞癌的分子机制[J]. 中国药物警戒, 2023, 20(9): 992-1001.

YANG Zhenzhen, CHANG Cheng, GAO Na, ZHANG Xiaolin, SONG Yinsen, LIU Ying, FAN Tianli. Molecular mechanism of luteolin for inhibiting esophageal squamous cell carcinoma based on network pharmacology and in vitro studies[J]. Chinese Journal of Pharmacovigilance, 2023, 20(9): 992-1001.

参考文献

[1] BRAY F, FERLAY J, SOERJOMATARAM I, et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424.
[2] SONG Y, LI L, OU Y, et al.Identification of genomic alterations in oesophageal squamous cell cancer[J]. Nature, 2014, 509(7498): 91-95.
[3] LAGERGREN J, SMYTH E, CUNNINGHAM D, et al.Oesophageal cancer[J]. Lancet, 2017, 390(10110): 2383-2396.
[4] IMRAN M, RAUF A, ABU-IZNEID T, et al.Luteolin, a flavonoid, as an anticancer agent: a review[J]. Biomed Pharmacother, 2019, 112: 108612.
[5] ZHU Y, CHEUNG ALM.Proteoglycans and their functions in esophageal squamous cell carcinoma[J]. World J Clin Oncol, 2021, 12(7): 507-521.
[6] NAKAMURA H, TAKADA K.Reactive oxygen species in cancer: current findings and future directions[J]. Cancer Sci, 2021, 112(10): 3945-3952.
[7] HUANG YJ.The effects and underlying mechanisms of resveratrol on sarcopenic obesity[D]. Chongqing: Army Medical University, 2019.
[8] ISMAIL T, KIM Y, LEE H, et al.Interplay between mitochondrial peroxiredoxins and ROS in cancer development and progression[J]. Int J Mol Sci, 2019, 20(18): 4407.
[9] AGGARWAL V, TULI HS, VAROL A, et al.Role of reactive oxygen species in cancer progression: molecular mechanisms and recent advancements[J]. Biomolecules, 2019, 9(11): 735.
[10] KWAK AW, LEE MJ, LEE MH, et al.The 3-deoxysappanchalcone induces ROS-mediated apoptosis and cell cycle arrest via JNK/p38 MAPKs signaling pathway in human esophageal cancer cells[J]. Phytomedicine, 2021, 86: 153564.
[11] KWAK AW, YOON G, LEE MH, et al.Picropodophyllotoxin, an epimer of podophyllotoxin, causes apoptosis of human esophageal squamous cell carcinoma cells through ROS-mediated JNK/P38 MAPK pathways[J]. Int J Mol Sci, 2020, 21(13): 4640.
[12] NOOROLYAI S, SHAJARI N, BAGHBANI E, et al.The relation between PI3K/AKT signalling pathway and cancer[J]. Gene, 2019, 698: 120-128.
[13] FRUMAN DA, CHIU H, HOPKINS BD, et al.The PI3K pathway in human disease[J]. Cell, 2017, 170(4): 605-635.
[14] MANNING BD, TOKER A.AKT/PKB signaling: navigating the network[J]. Cell, 2017, 169(3): 381-405.
[15] ZHOU S, GUO Z, ZHOU C, et al.Circ_NRIP1 is oncogenic in malignant development of esophageal squamous cell carcinoma (ESCC) via miR-595/SEMA4D axis and PI3K/AKT pathway[J]. Cancer Cell Int, 2021, 21(1): 250.
[16] XU JC, CHEN TY, LIAO LT, et al.NETO2 promotes esophageal cancer progression by inducing proliferation and metastasis via PI3K/AKT and ERK pathway[J]. Int J Biol Sci, 2021, 17(1): 259-270.
[17] KLEINSCHMIDT EG, SCHLAEPFER DD.Focal adhesion kinase signaling in unexpected places[J]. Curr Opin Cell Biol, 2017, 45: 24-30.
[18] CHEN J, ZHANG W, WANG Y, et al.The diacylglycerol kinase α (DGKα)/Akt/NF-κB feedforward loop promotes esophageal squamous cell carcinoma (ESCC) progression via FAK-dependent and FAK-independent manner[J]. Oncogene, 2019, 38(14): 2533-2550.
[19] FENG X, ARANG N, RIGIRACCIOLO DC, et al.A platform of synthetic lethal gene interaction networks reveals that the GNAQ uveal melanoma oncogene controls the hippo pathway through FAK[J]. Cancer Cell, 2019, 35(3): 457-472.
[20] SUN P, MA F, XU Y, et al.Genetic deletion of endothelial microRNA-15a/16-1 promotes cerebral angiogenesis and neurological recovery in ischemic stroke through Src signaling pathway[J]. J Cereb Blood Flow Metab, 2021, (10): 2725-2742.
[21] WANG R, WANG W, AO L, et al.Benzo[a]pyrene-7,8-diol-9,10-epoxide suppresses the migration and invasion of human extravillous trophoblast HTR-8/SVneo cells by down-regulating MMP2 through inhibition of FAK/SRC/PI3K/AKT pathway[J]. Toxicology, 2017, 386: 72-83.
[22] ZHANG L, ZHAO D, WANG Y, et al.Focal adhesion kinase (FAK) inhibitor-defactinib suppresses the malignant progression of human esophageal squamous cell carcinoma (ESCC) cells via effective blockade of PI3K/AKT axis and downstream molecular network[J]. Mol Carcinog, 2021, 60(2): 113-124.

基于网络药理学和体外研究探讨木犀草素抑制食管鳞状细胞癌的分子机制

Molecular mechanism of luteolin for inhibiting esophageal squamous cell carcinoma based on network pharmacology and in vitro studies

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

[1]	李嘉昕, 刘慧敏, 钱文秀, 马宁, 宋丽丽, 李遇伯. 基于中药系统毒理学数据库的中药致肾毒性及药物规律研究[J]. 中国药物警戒, 2024, 21(2): 173-180.
[2]	辛灵怡, 杨洋, 朱婧, 何娜, 张静媚, 王航天, 陈琴华, 杨光义. 重楼抗肿瘤活性成分分类及作用机制研究进展[J]. 中国药物警戒, 2024, 21(2): 235-240.
[3]	殷玉玲, 胡楚涓, 张晓朦, 王雨, 张冰, 林志健. 菊苣提取物抗阿霉素心脏毒性作用挖掘及验证[J]. 中国药物警戒, 2023, 20(8): 858-865.
[4]	梅雨, 朱越, 张慧婷, 肖成荣, 高月, 马增春. 基于网络药理学和实验验证探讨中药复方CB001对低剂量辐射防护的作用机制[J]. 中国药物警戒, 2023, 20(8): 872-879.
[5]	李亚梅, 水荣. 托法替尼治疗幼年特发性关节炎研究进展[J]. 中国药物警戒, 2023, 20(8): 956-960.
[6]	余悦华, 赵岩, 卢天公, 孙震晓. 基于EGFR的抗肺腺癌中药筛选及其体外作用研究[J]. 中国药物警戒, 2023, 20(7): 735-741.
[7]	陈林珍, 王璇, 张晓朦, 马志强, 陆珊, 吴嘉瑞, 赵崇军, 张冰. 基于斑马鱼模型的杠柳毒苷肝毒性评价[J]. 中国药物警戒, 2023, 20(7): 742-748.
[8]	苏月芬, 郑婧柔, 宫贺, 谢广通, 张洁, 赛春梅. 乳腺结重痛轻凝胶贴膏的成型性及治疗乳腺增生作用机制研究[J]. 中国药物警戒, 2023, 20(7): 783-790.
[9]	陈梦苹, 王雅欣, 姚荣妹, 包蕾, 赵荣华, 孙静, 耿子涵, 鲍岩岩, 戴敏, 郭姗姗, 崔晓兰. 基于网络药理学及实验验证探究清开灵软胶囊治疗冠状病毒肺炎的作用机制[J]. 中国药物警戒, 2023, 20(3): 253-257.
[10]	付昌丽, 陆苑, 陈思颖, 王永林, 李勇军, 王爱民, 刘春花. 红禾麻入血成分治疗类风湿性关节炎的作用机制[J]. 中国药物警戒, 2023, 20(2): 171-176.
[11]	王晓慧, 张帆, 夏文彬, 魏玉辉. 基于网络药理学和转录组学探讨京尼平致肝毒性机制[J]. 中国药物警戒, 2023, 20(2): 177-180.
[12]	曹琳, 冉峥, 侯强, 邱作成, 杨建华. 化铁丸化学成分分析及其防治乳腺增生的潜在机制预测[J]. 中国药物警戒, 2023, 20(10): 1113-1120.
[13]	王如梦, 郭梓琪, 杨宏新, 杨勇. 基于网络药理学及分子对接探讨荜茇治疗胃癌的作用机制研究[J]. 中国药物警戒, 2023, 20(10): 1121-1128.
[14]	李媛媛, 刘胜伟, 任忠洋, 丁玲, 刘洁, 廖原. 基于网络药理学探讨银杏叶治疗阿尔茨海默病的潜在作用机制[J]. 中国药物警戒, 2022, 19(9): 967-972.
[15]	汪祺, 文海若, 马双成. 以法尼醇X受体为作用靶点的何首乌中肝毒性成分的筛选[J]. 中国药物警戒, 2022, 19(6): 630-634.