Network Analysis Identifies Drug Targets and Small Molecules to Modulate Apoptosis Resistant Cancers.
Network Analysis Identifies Drug Targets and Small Molecules to Modulate Apoptosis Resistant Cancers.
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网络分析确定了药物靶标和小分子以调节抗细胞凋亡的癌症。
DOI：
10.3390/cancers13040851
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发表时间：
2021-02-18
期刊：
影响因子：
5.2
通讯作者：
Donakonda S
中科院分区：
文献类型：
--
作者：
Fathima S;Sinha S;Donakonda S
随着针对细胞凋亡的治疗策略的不断进化和逃避，对这些传统的癌症治疗方法进行重新定位已势在必行。在这项研究中，我们选择了一种芯片方法来挖掘必要的非凋亡细胞死亡基因。我们全面检查了三种预后不良的癌症：结肠癌、多形性胶质母细胞瘤和小细胞肺癌中广泛的蛋白质-蛋白质相互作用网络。我们的分析确定了非凋亡细胞死亡药物靶点。在许多顽固性癌症中，程序性细胞死亡或凋亡不能诱导细胞死亡。因此，有一个新兴的需要，以激活交替的细胞死亡途径在这类癌症。在这项研究中，我们分析了抗凋亡结肠癌、多形性胶质母细胞瘤和小细胞肺癌的转录组谱。我们从每种癌症中提取了非凋亡细胞死亡基因簇，以了解受这些基因影响的功能网络及其在细胞凋亡失败时诱导细胞死亡的作用。我们确定了调节细胞死亡基因的转录因子和蛋白质-蛋白质相互作用网络，以了解它们在调节细胞死亡机制中的作用。网络拓扑分析发现FANCD2（铁下垂，负调节因子，向下）、NCOA4（铁下垂，向上）、IKBKB（碱下垂，向下）和RHOA（内源性细胞死亡，向下）分别是结肠腺癌、多形性胶质母细胞瘤、小细胞肺癌表型的潜在药物靶点。我们还评估了miRNA与药物靶点的关联。基于药物-靶标相互作用网络的通路信息，我们确定了肿瘤生长相关的相互作用伙伴。药物靶点和相互作用蛋白之间的蛋白-蛋白相互作用结合位点提供了一个机会来识别在每种癌症中可以调节功能性细胞死亡相互作用活性的小分子。总的来说，我们对非凋亡细胞死亡相关基因的系统筛选发现了有助于癌症治疗的靶点。
With the thriving efficacy of cancers to evolve and evade treatment strategies targeting the apoptosis cell death mechanism, it has become imperative to reorient these conventional cancer therapy methods. In this study, we opted for an in-silico approach to mine the essential non-apoptotic cell death genes. We holistically examined the extensive protein–protein interaction networks in three such cancers with poor prognosis: colon adenocarcinoma, glioblastoma multiforme, and small cell lung cancer. Our analysis identified non-apoptotic cell death drug targets. Programed cell death or apoptosis fails to induce cell death in many recalcitrant cancers. Thus, there is an emerging need to activate the alternate cell death pathways in such cancers. In this study, we analyzed the apoptosis-resistant colon adenocarcinoma, glioblastoma multiforme, and small cell lung cancers transcriptome profiles. We extracted clusters of non-apoptotic cell death genes from each cancer to understand functional networks affected by these genes and their role in the induction of cell death when apoptosis fails. We identified transcription factors regulating cell death genes and protein–protein interaction networks to understand their role in regulating cell death mechanisms. Topological analysis of networks yielded FANCD2 (ferroptosis, negative regulator, down), NCOA4 (ferroptosis, up), IKBKB (alkaliptosis, down), and RHOA (entotic cell death, down) as potential drug targets in colon adenocarcinoma, glioblastoma multiforme, small cell lung cancer phenotypes respectively. We also assessed the miRNA association with the drug targets. We identified tumor growth-related interacting partners based on the pathway information of drug-target interaction networks. The protein–protein interaction binding site between the drug targets and their interacting proteins provided an opportunity to identify small molecules that can modulate the activity of functional cell death interactions in each cancer. Overall, our systematic screening of non-apoptotic cell death-related genes uncovered targets helpful for cancer therapy.
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影响因子：
--
作者：
Das J;Yu H
通讯作者：
Yu H
影响因子：
4.6
作者：
Kivimäki I;Lebichot B;Saramäki J;Saerens M
通讯作者：
Saerens M
DOI：
10.2741/3297
发表时间：
2009-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
David KK;Andrabi SA;Dawson TM;Dawson VL
通讯作者：
Dawson VL
影响因子：
14.9
作者：
Han H;Cho JW;Lee S;Yun A;Kim H;Bae D;Yang S;Kim CY;Lee M;Kim E;Lee S;Kang B;Jeong D;Kim Y;Jeon HN;Jung H;Nam S;Chung M;Kim JH;Lee I
通讯作者：
Lee I
影响因子：
14.9
作者：
Gaulton A;Hersey A;Nowotka M;Bento AP;Chambers J;Mendez D;Mutowo P;Atkinson F;Bellis LJ;Cibrián-Uhalte E;Davies M;Dedman N;Karlsson A;Magariños MP;Overington JP;Papadatos G;Smit I;Leach AR
通讯作者：
Leach AR