Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea.
College of Medicine, Hanyang University, Seoul, 04763, South Korea.
Cancer Chemother Pharmacol. 2020 Apr;85(4):627-639. doi: 10.1007/s00280-020-04046-8. Epub 2020 Mar 7.
Drug resistance is a well-known phenomenon leading to a reduction in the effectiveness of pharmaceutical treatments. Resistance to chemotherapeutic agents can involve various intrinsic cellular processes including drug efflux, increased resistance to apoptosis, increased DNA damage repair capabilities in response to platinum salts or other DNA-damaging drugs, drug inactivation, drug target alteration, epithelial-mesenchymal transition (EMT), inherent cell heterogeneity, epigenetic effects, or any combination of these mechanisms. Deubiquitinating enzymes (DUBs) reverse ubiquitination of target proteins, maintaining a balance between ubiquitination and deubiquitination of proteins to maintain cell homeostasis. Increasing evidence supports an association of altered DUB activity with development of several cancers. Thus, DUBs are promising candidates for targeted drug development. In this review, we outline the involvement of DUBs, particularly ubiquitin-specific proteases, and their roles in drug resistance in different types of cancer. We also review potential small molecule DUB inhibitors that can be used as drugs for cancer treatment.
耐药性是导致药物治疗效果降低的一个众所周知的现象。对化疗药物的耐药性可能涉及各种内在的细胞过程，包括药物外排、对细胞凋亡的抵抗力增加、对铂盐或其他破坏 DNA 的药物的 DNA 损伤修复能力增加、药物失活、药物靶点改变、上皮-间充质转化（EMT）、固有细胞异质性、表观遗传效应，或这些机制的任何组合。去泛素化酶（DUB）逆转靶蛋白的泛素化，在蛋白质的泛素化和去泛素化之间保持平衡，以维持细胞内稳态。越来越多的证据支持 DUB 活性改变与多种癌症的发生有关。因此，DUB 是靶向药物开发的有前途的候选者。在这篇综述中，我们概述了 DUBs（特别是泛素特异性蛋白酶）的参与及其在不同类型癌症中的耐药作用。我们还回顾了潜在的小分子 DUB 抑制剂，可作为癌症治疗药物。
