Network Pharmacology-Based Approach to Investigate the Molecular Targets of Sinomenine for Treating Breast Cancer.
Network Pharmacology-Based Approach to Investigate the Molecular Targets of Sinomenine for Treating Breast Cancer.
复制标题
基于网络药理学的方法研究青藤碱治疗乳腺癌的分子靶点。
DOI：
10.2147/cmar.s282684
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发表时间：
2021
影响因子：
3.3
通讯作者：
Yu B
中科院分区：
文献类型：
--
作者：
Li XM;Li MT;Jiang N;Si YC;Zhu MM;Wu QY;Shi DC;Shi H;Luo Q;Yu B
已知青藤碱可以抑制乳腺癌细胞的增殖。然而，其目标尚未找到。本研究旨在通过网络药理学寻找青藤碱治疗乳腺癌的分子靶点。从指定数据库中单独筛选青藤碱或乳腺癌的潜在靶点。青藤碱与乳腺癌的共同靶点被认为是青藤碱治疗乳腺癌的靶点。根据京都基因与基因组百科全书（KEGG）通路富集分析结果，构建了青藤碱-靶点-通路网络。通过蛋白质-蛋白质相互作用（PPI）分析和分子对接进一步确定了青藤碱的假定靶点。最后，假定的目标在体外和体内得到验证。通过网络药理学分析确定了二十个预测靶标。基因本体（GO）和KEGG通路富集表明，这些预测靶标在MAP激酶活性、VEGF信号通路、松弛素信号通路、生长激素合成、分泌和作用过程中富集。通过 PPI 和分子对接分析，进一步将 MAPK1、NOS3、NR3C1、NOS1 和 NOS2 确定为假定靶点。 MCF-7细胞和MDA-MB-231细胞中MAPK1、NR3C1、NOS1、NOS2和NOS3基因的表达均受到青藤碱的显着调节。此外，NR3C1在人乳腺癌标本中的表达低于瘤旁正常组织。同时，青藤碱处理后异种移植肿瘤中NR3C1的表达上调。 MAPK1、NR3C1、NOS1、NOS2 和 NOS3 被确定为青藤碱治疗乳腺癌的假定靶点。在两种乳腺癌细胞系、异种移植肿瘤模型和人乳腺癌标本中初步证实NR3C1是青藤碱的靶点。这些数据表明，基于网络药理学的青藤碱治疗乳腺癌靶点预测是可靠的。
Sinomenine has been known to inhibit the proliferation of breast cancer cells. However, its targets have not been found yet. This study aimed to search for molecular targets of sinomenine for treating breast cancer via network pharmacology. Potential targets of sinomenine or breast cancer were separately screened from indicated databases. The common targets of both sinomenine and breast cancer were considered as the targets of sinomenine for treating breast cancer. A sinomenine-target-pathway network was constructed based on the obtained results from Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The putative targets of sinomenine were further determined by using protein–protein interaction (PPI) analysis and molecular docking. Finally, the putative targets were verified in vitro and in vivo. Twenty predicted targets were identified through network pharmacological analysis. Gene Ontology (GO) and KEGG pathway enrichment indicated that these predicted targets enriched in the process of MAP kinase activity, VEGF signaling pathway, Relaxin signaling pathway, Growth hormone synthesis, secretion and action. MAPK1, NOS3, NR3C1, NOS1 and NOS2 were further identified as the putative targets by using PPI and molecular docking analysis. Expression of MAPK1, NR3C1, NOS1, NOS2 and NOS3 genes were significantly regulated by sinomenine in both MCF-7 cells and MDA-MB-231 cells. Furthermore, the expression of NR3C1 in human breast cancer specimens was lower than that in para-tumor normal tissues. Meanwhile, the expression of NR3C1 in xenograft tumors was up-regulated after sinomenine treatment. MAPK1, NR3C1, NOS1, NOS2 and NOS3 were identified as the putative targets of sinomenine for treating breast cancer. NR3C1 was preliminarily confirmed as a target of sinomenine in two breast cancer cell lines, xenograft tumor models and human breast cancer specimens. These data indicated that the network pharmacology-based prediction of sinomenine targets for treating breast cancer could be reliable.