Molecular Pathways: Translational Potential of Deubiquitinases as Drug Targets
Molecular Pathways: Translational Potential of Deubiquitinases as Drug Targets
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DOI：
10.1158/1078-0432.ccr-14-0568
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发表时间：
2014-08-01
影响因子：
11.5
通讯作者：
Linder, Stig
中科院分区：
文献类型：
--
作者：
D'Arcy, Padraig;Linder, Stig
泛素蛋白酶体系统(UPS)是控制蛋白质降解的主要系统，也是细胞基本过程的关键调节因子。癌细胞对功能正常的UPS的依赖，加上Bortezomib治疗多发性骨髓瘤的临床成功，使UPS成为药物开发的明显目标。去泛素酶(DUB)是UPS的组成部分，它包括一系列不同的泛素异肽酶家族，催化从靶蛋白或多泛素链中去除泛素部分，导致信号改变或蛋白质稳定性的改变。越来越多的证据表明，在癌症的发生和发展中，DUB活性的放松调控。在许多肿瘤中观察到的DUB表达模式的改变可以潜在地作为预测疾病结果和治疗反应的临床标志物。DUB在肿瘤细胞中过表达的发现表明，它们可能成为抗癌治疗的新靶点。几种特定和广谱的DUB抑制剂在临床前的体内模型中被证明具有抗肿瘤活性，全身毒性水平较低。未来的研究有望确定DUB抑制剂作为一种治疗癌症的策略的临床潜力。(C)2014年AACR。
The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS coupled with the clinical success of bortezomib for the treatment of multiple myeloma have made the UPS an obvious target for drug development. Deubiquitinases (DUB) are components of the UPS that encompass a diverse family of ubiquitin isopeptidases that catalyze the removal of ubiquitin moieties from target proteins or from polyubiquitin chains, resulting in altered signaling or changes in protein stability. Increasing evidence has implicated deregulation of DUB activity in the initiation and progression of cancer. The altered pattern of DUB expression observed in many tumors can potentially serve as a clinical marker for predicting disease outcome and therapy response. The finding of DUB overexpression in tumor cells suggests that they may serve as novel targets for the development of anticancer therapies. Several specific and broad-spectrum DUB inhibitors are shown to have antitumor activity in preclinical in vivo models with low levels of systemic toxicity. Future studies will hopefully establish the clinical potential for DUB inhibitors as a strategy to treat cancer. (C) 2014 AACR.