Zou Dan, Bai Jin, Lu Enting, Yang Chunjiao, Liu Jiaqing, Wen Zhenpeng, Liu Xuqin, Jin Zi, Xu Mengdan, Jiang Lei, Zhang Ye, Zhang Yi
The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China.
Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.
Front Oncol. 2021 Oct 21;11:745590. doi: 10.3389/fonc.2021.745590. eCollection 2021.
Epithelial ovarian cancer (EOC) has a poor prognosis and high mortality rate; patients are easy to relapse with standard therapies. So, there is an urgent need to develop novel drugs. In this study, differentially expressed genes (DEGs) of EOC were identified in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Enrichment and protein-protein interaction (PPI) analyses were performed. The drug candidate which has the possibility to treat EOC was predicted by Connectivity Map (CMAP) databases. Moreover, molecular docking was selected to calculate the binding affinity between drug candidate and hub genes. The cytotoxicity of drug candidates was assessed by MTT and colony formation analysis, the proteins coded by hub genes were detected by Western blots, and apoptosis analysis was evaluated by flow cytometry. Finally, 296 overlapping DEGs (|log 2 fold change|>1; q-value <0.05), which were principally involved in the cell cycle (p < 0.05), and cyclin-dependent kinase 1 (CDK1) were screened as the significant hub gene from the PPI network. Furthermore, the 21 drugs were extracted from CMAPs; among them, piperlongumine (PL) showed a lower CMAP score (-0.80, -62.92) and was regarded as the drug candidate. Furthermore, molecular docking results between PL and CDK1 with a docking score of -8.121 kcal/mol were close to the known CDK1 inhibitor (-8.24 kcal/mol). Additionally, experiments showed that PL inhibited proliferation and induced apoptosis targeting CDK1 in EOC SKOV3 cells. Our results reveal that PL may be a novel drug candidate for EOC by inhibiting cell cycle.
上皮性卵巢癌（EOC）预后较差且死亡率高；患者采用标准疗法后容易复发。因此，迫切需要开发新型药物。在本研究中，在癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）中鉴定了EOC的差异表达基因（DEG）。进行了富集分析和蛋白质-蛋白质相互作用（PPI）分析。通过连通性图谱（CMAP）数据库预测了有可能治疗EOC的候选药物。此外，选择分子对接来计算候选药物与枢纽基因之间的结合亲和力。通过MTT和集落形成分析评估候选药物的细胞毒性，通过蛋白质印迹法检测枢纽基因编码的蛋白质，并通过流式细胞术评估细胞凋亡分析。最后，从PPI网络中筛选出296个重叠的DEG（|log2倍数变化|>1；q值<0.05），这些DEG主要参与细胞周期（p<0.05），细胞周期蛋白依赖性激酶1（CDK1）被筛选为重要的枢纽基因。此外，从CMAP中提取了21种药物；其中，荜茇酰胺（PL）显示出较低的CMAP评分（-0.80，-62.92），被视为候选药物。此外，PL与CDK1之间的分子对接结果显示对接分数为-8.121 kcal/mol，与已知的CDK1抑制剂（-8.24 kcal/mol）接近。此外，实验表明PL通过靶向EOC SKOV3细胞中的CDK1抑制增殖并诱导凋亡。我们的结果表明，PL可能通过抑制细胞周期成为EOC的新型候选药物。
