Although more traditionally associated with degradation and maintenance of protein homeostasis, the ubiquitin-proteasome system (UPS) has emerged as a critical component in the regulation of cancer cell growth and survival. The development of inhibitors that block the proteolytic activities of the proteasome have highlighted its suitability as a bona fide anti-cancer drug target. However, key determinants including the development of drug resistance and dose-limiting toxicity call for the identification of alternative components of the UPS for novel drug targeting. Recently the deubiquitinases (DUBs), a diverse family of enzymes that catalyze ubiquitin removal, have attracted significant interest as targets for the development of next generation UPS inhibitors. In particular, pharmacological inhibition of the proteasomal cysteine DUBs (i.e., USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells and inhibit tumour growth in several in vivo models. In the current review we focus on the modes of action of proteasome DUB inhibitors and discus the potential of DUB inhibitors to circumvent acquired drug resistance and provide a therapeutic option for the treatment of cancer.

中文翻译：

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抑制蛋白酶体去泛素酶活性：克服对常规蛋白酶体抑制剂耐药性的策略？

尽管在传统上与蛋白质稳态的降解和维持有关，但泛素-蛋白酶体系统（UPS）已成为调节癌细胞生长和存活的重要组成部分。阻断蛋白酶体蛋白水解活性的抑制剂的开发突显了其作为真正的抗癌药物靶标的适用性。但是，包括耐药性和剂量限制性毒性的发展在内的关键决定因素要求确定用于新型药物靶向的UPS的替代成分。最近，去泛素化酶（DUBs）是催化泛素去除的多种酶，已引起广泛兴趣，成为开发下一代UPS抑制剂的目标。特别是蛋白酶体半胱氨酸DUB的药理抑制作用（即 在几种体内模型中，USP14和UCHL5）已显示出对癌细胞特别的细胞毒性，并抑制肿瘤的生长。在当前的审查中，我们专注于蛋白酶体DUB抑制剂的作用方式，并探讨了DUB抑制剂规避获得性耐药的潜力，并为癌症的治疗提供了选择。