基于网络药理学探究山莴苣素抗宫颈癌的作用机制  

To explore anti-cervical cancer mechanism of lactucin based on network pharmacology

作　　者：王梦姣 刘通 努尔曼古丽·买买提明 米娜 阿吉艾克拜尔·艾萨[1,2] 杨建 WANG Mengjiao;LIU Tong;Nuermanguli Maimaitiming;MI Na;Ajiaikebaier Aisa;YANG Jian(School of Pharmacy,Xinjiang Medical University,Urumqi 830017,China;Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology,Urumqi 830017,China;State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseasees in Central Asia,Research Institute of Clinical Medicine,First Affiliated Hospital of Xinjiang Medical University,Urumqi 830054,China)

机构地区：[1]新疆医科大学药学院,乌鲁木齐830017 [2]新疆天然药物活性组分与释药技术重点实验室,乌鲁木齐830017 [3]新疆医科大学第一附属医院临床医学研究院省部共建中亚高发病成因与防治国家重点实验室,乌鲁木齐830054

出　　处：《新疆医科大学学报》2025年第4期522-529,共8页Journal of Xinjiang Medical University

基　　金：国家自然科学基金(82360721);中亚高发病分子细胞前沿创新研究平台建设项目(ZYYD2024JD01)。

摘　　要：目的通过网络药理学及体外实验探究毛菊苣倍半萜成分山莴苣素治疗宫颈癌的作用靶点及作用机制。方法通过PubChem和PharmMapper数据库获取山莴苣素的对应靶点,采用GeneCards和DrugBank数据库获取宫颈癌的有关靶点,运用Venny 2.1.0在线工具绘制山莴苣素和宫颈癌靶点韦恩图,通过STRING数据库构建靶点相互作用网络,利用Cytoscape 3.9.1软件构建“宫颈癌-靶点-山莴苣素”网络图。通过基因富集分析在线工具Metascape数据库对潜在靶标进行基因本体(Gene ontology,GO)功能富集及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)通路富集分析,采用AutoDock软件对关键成分和核心靶点进行分子对接。通过Cell Counting Kit-8(CCK-8)细胞增殖实验检测山莴苣素对Hela细胞存活率的影响,免疫印迹法(Western blot)探索山莴苣素对Akt/mTOR信号通路关键蛋白的影响,细胞迁移实验检测山莴苣素对Hela细胞迁移能力的影响。结果经数据库查找获得山莴苣素相关靶点221个,宫颈癌潜在靶点1367个,利用韦恩图获得73个共有靶点,通过构建蛋白质-蛋白质互作网络和degree值筛选得到6个核心靶点:AKT1、CASP3、EGFR、ESR1、HSP90AA1、MMP9。GO和KEGG富集分析表明,磷脂酰肌醇三激酶(PI3K)/蛋白激酶B(Akt)通路在山莴苣素治疗宫颈癌中起着关键作用。分子对接结果显示,山莴苣素和AKT1等靶点有良好的结合能力。细胞增殖实验结果显示,20~160μmol/L的浓度范围内,山莴苣素抑制Hela宫颈癌细胞的增殖,半抑制浓度(IC 50)值为113.1μmol/L。Western blot结果表明,与对照组相比,山莴苣素抑制AKT蛋白的磷酸化及降低p-mTOR/mTOR、p-p70S6K和p-AKT/AKT的表达水平,差异有统计学意义(P<0.01)。细胞迁移实验结果显示,与对照组相比,山莴苣素低、中、高浓度组Hela细胞迁移愈合率降低,愈合率降低水平与山莴苣素浓度成正比,差异有统计学意义(P<0.0001Objective To investigate the target and mechanism of action of lactucin,a sesquiterpene constituent of Cichorium glandulosum Boiss.et Huet,in the treatment of cervical cancer by network pharmacology and in vitro experiments.Methods The corresponding targets of lactucin were obtained from PubChem and PharmMapper databases,and the targets of cervical cancer were obtained from GeneCards and DrugBank databases,and the Venn diagram of lactucin targets and targets of cervical cancer were plotted using the Venny 2.1.0 online tool,and the target interaction network was constructed from the STRING database,and Cytoscape 3.9.1 software was used to construct the network diagram of"cervical cancer-target-lactucin".The Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment of potential targets were analyzed by Metascape database,and molecular docking of key components and core targets were performed by AutoDock software.The effects of lactucin on the survival rate of Hela cells were detected by CCK-8 cell proliferation assay,the effect of lactucin on the key proteins of the Akt/mTOR signaling pathway was explored by Western blot assay,and the effect of lactucin on the migratory ability of Hela cells was detected by cell migration assay.Results After searching the database,we obtained 221 lactucin related targets,1367 potential targets in cervical cancer,73 common targets by using the Venn diagram,and 6 core targets by protein-protein interactin network and degree value screening:AKT1,CASP3,EGFR,ESR1,HSP90AA1 and MMP9.GO and KEGG enrichment analysis showed that the phosphatidylinositol trikinase(PI3K)/protein kinase B(Akt)pathway played a key role in the treatment of cervical cancer with lactucin.The molecular docking results showed that lactucin had good ability AKT1 and other targets.The cell proliferation assay showed that lactucin can inhibit the proliferation of Hela cervical cancer cells in the concentration range of 20-160μmol/L,and the half maximal inhibitory concentration(IC 50)value was

关 键 词：山莴苣素 宫颈癌 网络药理学 分子对接 蛋白激酶B信号通路 

分 类 号：R965[医药卫生—药理学]