姜黄素抗结直肠癌的线粒体生物学作用机制研究  

Study on Mechanism of Anti-Colorectal Cancer Effect of Curcumin Based on Network Pharmacology

作　　者：力海伦 付志强 孙司正 郭文文[1] 何震宇[1] LI Hailun;FU Zhiqiang;SUN Sizheng;GUO Wenwen;HE Zhenyu(The Second Affiliated Hospital of Nanjing Medical University,Nanjing 210011,China)

机构地区：[1]南京医科大学第二附属医院,江苏南京210011

出　　处：《肿瘤学杂志》2023年第8期673-680,共8页Journal of Chinese Oncology

基　　金：南京市2018年度科技发展计划项目(201803042)。

摘　　要：[目的]基于分子对接技术和体外细胞实验探讨姜黄素抗结直肠癌的线粒体作用机制。[方法]SwissTargetPrediction、HERB、DisGeNET、GeneCards数据库挖掘姜黄素抗结直肠癌的交集靶点后,利用cytoscapehubba_MCC、MCN方法筛选核心靶点;使用STRING、AutoDock分别构建靶点蛋白互作网络和姜黄素-核心靶点对接;体外培养细胞模型验证姜黄素线粒体功能核心靶点生物学作用。[结果]网络药理学预测共得到49个姜黄素抗结直肠癌的交集靶点,cytohubba计算互作关系获得9个核心靶点,为MMP2、IL-17A、HIF-1α、TNF、CYP19A1、CD44、BCL-2L11、RICTOR和BECN1,其中2/3的靶点是线粒体功能关联靶蛋白。分子对接结果显示姜黄素与线粒通路蛋白结合稳定。体外细胞模型验证结果表明姜黄素以剂量依赖方式抑制SW480和HCT116细胞增殖。q-PCR实验证明姜黄素导致SW480细胞SIRT1、Hsp60基因表达升高(P<0.05),SIRT3、COX1、ND1、OPA1、MFN2、POLG、MTH1基因表达降低(P<0.05)。Western blot结果显示姜黄素可明显抑制VDAC、COXIV蛋白的表达(P<0.01),升高ATG7蛋白表达(P<0.01)。[结论]姜黄素可多靶点介导线粒体功能障碍,促进结直肠癌细胞凋亡。[Objective]To explore the mechanism of anti-colorectal cancer effect of Curcumin based on network pharmacology.[Methods]The intersection targets of Curcumin against colorectal cancer were mined in SwissTargetPrediction,HERB,DisGeNET and GeneCards databases.The core targets were screened by Cytoscape Hubba_MCC and MCN methods,the target protein interaction network and the core target docking were constructed by STRING and AutoDock,respectively,and the biological effects of Curcumin mitochondrial core targets were verified by cell model in vitro.[Results]A total of 49 intersection targets of Curcumin against colorectal cancer were obtained by network pharmacology prediction,and 9 core target interactions(MMP2,IL-17A,HIF-1α,TNF,CYP19A1,CD44,BCL-2L11,RICTOR,BECN1)were obtained by cytohubba,of which 2/3 targets were mitochondrial function related proteins.The results of molecular docking showed that the binding of Curcumin to mitochondrial pathway proteins was stable.The results of cell model verification in vitro showed that Curcumin inhibited the proliferation of SW480 and HCT116 cells in a dose-dependent manner.The qRT-PCR assay showed that Curcumin increased the expression of SIRT1 and Hsp60(P<0.05),decreased the expression of SIRT3,COX1,ND1,OPA1,MFN2,POLG and MTH1(P<0.05)in SW480 cells.Western-blot showed that Curcumin significantly inhibited the expression of VDAC and COXIV proteins and increase the expression of ATG7 protein(P<0.01).[Conclusion]Curcumin can promote apoptosis of colorectal cancer cells through multi-target-mediated mitochondrial dysfunction.

关 键 词：姜黄素 结直肠癌 网络药理学 线粒体 分子对接 

分 类 号：R735.35[医药卫生—肿瘤] R735.37[医药卫生—临床医学]