Functional network analysis reveals potential repurposing of β-blocker atenolol for pancreatic cancer therapy
Functional network analysis reveals potential repurposing of β-blocker atenolol for pancreatic cancer therapy
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DOI：
10.1007/s40199-020-00375-4
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发表时间：
2020-10-23
影响因子：
3.6
通讯作者：
Utomo，Rohmad Yudi
中科院分区：
文献类型：
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作者：
Hermawan，Adam;Putri，Herwandhani;Utomo，Rohmad Yudi
背景胰腺癌患者的生存率低，因此需要不断发现和开发新的胰腺癌药物。功能网络分析是一种基于基因、靶点和疾病网络相互作用的生物信息学方法，广泛应用于药物发现和开发。直接靶蛋白（DTP）和间接靶蛋白（ITPs）可以被重新用于胰腺癌的治疗，使用功能网络分析。分别从STITCH和STRING数据库获得。Atenolol介导的蛋白质（AMP）收集DTP和ITP和进一步分析基因本体，KEGG途径富集，遗传变异，总生存，和分子对接.ResultsWe获得了176 AMP，包括10 DTP和166 ITP。在参与胰腺癌途径的AMP中，鉴定了几种AMP，如MAPK 1、RELA、MAPK 8、STAT 1和STAT 3。在0.9%-16%的患者中发现了7种AMP的遗传变异。MAPK 1、RELA、STAT 3、GNB 1和MMP 9 mRNA水平高的患者总生存率明显低于低表达的患者。分子对接研究表明，RELA和MMP 9是阿替洛尔治疗胰腺癌的潜在靶点。结论阿替洛尔可能通过调节MMP 9和NF-κB信号通路而靶向胰腺癌细胞。本研究的结果需要进一步的体外和体内验证。图形摘要
BackgroundThe survival rate of patients with pancreatic cancer is low; therefore, continuous discovery and development of novel pancreatic cancer drugs are required. Functional network analysis is an integrated bioinformatics approach based on gene, target, and disease networks interaction, and it is extensively used in drug discovery and development.ObjectiveThis study aimed to identify if atenolol, a selective adrenergic inhibitor, can be repurposed for the treatment of pancreatic cancer using functional network analysis.MethodsDirect target proteins (DTPs) and indirect target proteins (ITPs) were obtained from STITCH and STRING databases, respectively. Atenolol-mediated proteins (AMPs) were collected from DTPs and ITPs and further analyzed for gene ontology, KEGG pathway enrichment, genetic alterations, overall survival, and molecular docking.ResultsWe obtained 176 AMPs that consisted of 10 DTPs and 166 ITPs. Among the AMPs involved in the pancreatic cancer pathways, several AMPs such as MAPK1, RELA, MAPK8, STAT1, and STAT3 were identified. Genetic alterations in seven AMPs were identified in 0.9%–16% of patients. Patients with high mRNA levels ofMAPK1,RELA,STAT3,GNB1, andMMP9had significantly worse overall survival rates compared with patients with low expression. Molecular docking studies showed that RELA and MMP9 are potential target candidates of atenolol in the treatment of patients with pancreatic cancer.ConclusionIn conclusion, atenolol can potentially be repurposed to target pancreatic cancer cells by modulating MMP9 and NF-κB signaling. The results of this study need to be further validated in vitro and in vivo.Graphical abstract