Fathima Samreen, Sinha Swati, Donakonda Sainitin
Department of Biotechnology, Faculty of Life and Allied Health Sciences, MS Ramaiah University of Applied Sciences, Bengaluru 560054, India.
School of Medicine, Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts Der Isar, Technical University of Munich, 81675 Munich, Germany.
Cancers (Basel). 2021 Feb 18;13(4):851. doi: 10.3390/cancers13040851.
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.
程序性细胞死亡或凋亡在许多难治性癌症中无法诱导细胞死亡。因此，在这类癌症中激活替代细胞死亡途径的需求日益凸显。在本研究中，我们分析了抗凋亡的结肠腺癌、多形性胶质母细胞瘤和小细胞肺癌的转录组图谱。我们从每种癌症中提取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，以及当凋亡失败时它们在诱导细胞死亡中的作用。我们鉴定了调控细胞死亡基因的转录因子和蛋白质 - 蛋白质相互作用网络，以了解它们在调控细胞死亡机制中的作用。网络的拓扑分析分别得出FANCD2（铁死亡，负调节因子，下调）、NCOA4（铁死亡，上调）、IKBKB（碱中毒性细胞死亡，下调）和RHOA（内吞性细胞死亡，下调）作为结肠腺癌、多形性胶质母细胞瘤、小细胞肺癌表型中的潜在药物靶点。我们还评估了miRNA与药物靶点的关联。我们根据药物 - 靶点相互作用网络的通路信息鉴定了与肿瘤生长相关的相互作用伙伴。药物靶点与其相互作用蛋白之间的蛋白质 - 蛋白质相互作用结合位点为鉴定能够调节每种癌症中功能性细胞死亡相互作用活性的小分子提供了机会。总体而言，我们对非凋亡细胞死亡相关基因的系统筛选揭示了有助于癌症治疗的靶点。
