PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Academia Sinica, Taipei 11031, Taiwan.
Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
Int J Mol Sci. 2021 May 31;22(11):5895. doi: 10.3390/ijms22115895.
Ovarian cancer is often detected at the advanced stages at the time of initial diagnosis. Early-stage diagnosis is difficult due to its asymptomatic nature, where less than 30% of 5-year survival has been noticed. The underlying molecular events associated with the disease's pathogenesis have yet to be fully elucidated. Thus, the identification of prognostic biomarkers as well as developing novel therapeutic agents for targeting these markers become relevant. Herein, we identified 264 differentially expressed genes (DEGs) common in four ovarian cancer datasets (GSE14407, GSE18520, GSE26712, GSE54388), respectively. We constructed a protein-protein interaction (PPI) interaction network with the overexpressed genes (72 genes) and performed gene enrichment analysis. In the PPI networks, three proteins; TTK Protein Kinase (TTK), NIMA Related Kinase 2 (NEK2), and cyclin-dependent kinase (CDK1) with higher node degrees were further evaluated as therapeutic targets for our novel multi-target small molecule NSC777201. We found that the upregulated DEGs were enriched in KEGG and gene ontologies associated with ovarian cancer progression, female gamete association, otic vesicle development, regulation of chromosome segregation, and therapeutic failure. In addition to the PPI network, ingenuity pathway analysis also implicate TTK, NEK2, and CDK1 in the elevated salvage pyrimidine and pyridoxal pathways in ovarian cancer. The TTK, NEK2, and CDK1 are over-expressed, demonstrating a high frequency of genetic alterations, and are associated with poor prognosis of ovarian cancer cohorts. Interestingly, NSC777201 demonstrated anti-proliferative and cytotoxic activities (GI = 1.6 µM1.82 µM and TGI = 3.5 µM3.63 µM) against the NCI panels of ovarian cancer cell lines and exhibited a robust interaction with stronger affinities for TTK, NEK2, and CDK1, than do the standard drug, paclitaxel. NSC777201 displayed desirable properties of a drug-like candidate and thus could be considered as a novel small molecule for treating ovarian carcinoma.
卵巢癌在初始诊断时通常处于晚期。由于其无症状性质，早期诊断较为困难，只有不到 30%的患者有 5 年生存率。疾病发病机制相关的潜在分子事件尚未完全阐明。因此，鉴定预后生物标志物以及开发针对这些标志物的新型治疗药物变得至关重要。在此，我们分别在四个卵巢癌数据集（GSE14407、GSE18520、GSE26712、GSE54388）中鉴定了 264 个差异表达基因（DEGs）。我们构建了一个过表达基因（72 个基因）的蛋白质-蛋白质相互作用（PPI）网络，并进行了基因富集分析。在 PPI 网络中，三个具有更高节点度的蛋白质，即 TTK 蛋白激酶（TTK）、NIMA 相关激酶 2（NEK2）和细胞周期蛋白依赖性激酶 1（CDK1），被进一步评估为我们新型多靶小分子 NSC777201 的治疗靶点。我们发现上调的 DEGs 在与卵巢癌进展、女性配子体关联、耳囊发育、染色体分离调控和治疗失败相关的 KEGG 和基因本体论中富集。除了 PPI 网络，通路分析还表明 TTK、NEK2 和 CDK1 在卵巢癌中升高的补救嘧啶和吡哆醛途径中发挥作用。TTK、NEK2 和 CDK1 过表达，表现出高频的遗传改变，并与卵巢癌队列的不良预后相关。有趣的是，NSC777201 对卵巢癌 NCI 细胞系表现出抗增殖和细胞毒性活性（GI = 1.6 µM1.82 µM 和 TGI = 3.5 µM3.63 µM），并与标准药物紫杉醇相比，与 TTK、NEK2 和 CDK1 具有更强的亲和力。NSC777201 表现出类药候选物的理想特性，因此可被认为是治疗卵巢癌的新型小分子药物。
