卵巢癌中的去泛素酶:在抗药性和肿瘤侵袭性中的作用

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.100355
Giovanni Luca Beretta, Matteo Costantino, Luca Mirra, Pietro Pettinari, Paola Perego
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引用次数: 0

摘要

卵巢癌是一种致命性疾病,原因是诊断较晚和出现耐药性,从而限制了以铂为基础的疗法的疗效。耐药机制包括肿瘤内在因素和肿瘤微环境相关因素。去泛素酶(DUBs)在卵巢癌中的作用开始显现。DUBs是一个庞大的酶家族,能清除靶蛋白上的泛素,并参与DNA损伤修复和细胞凋亡等影响耐药性的过程。此外,DUBs 还能调节有利于免疫抑制微环境的 T 细胞群的功能。有三种 DUB 与蛋白酶体相关,而绝大多数不相关。在前一种 DUBs 中,USP14 被认为可调节 Bcl6 和 BACH1 等转录因子。此外,RPN11/PSD14 还能干扰包括上皮间质转化在内的各种过程,而 USP1 等非蛋白酶体 DUBs 也能通过作用于蜗牛(Snail)来实现上皮间质转化。此外,USP8 通过稳定 HER 家族受体可产生耐药性。总的来说,DUBs 似乎是可以药物治疗的,有几种抑制剂正在开发中。基于 DUBs 的生物学作用,DUBs 靶向似乎很有希望成为涉及不同治疗方法的组合策略。在此,我们总结了 DUBs 与卵巢癌的相关性,并深入探讨了治疗这种疾病的未来挑战。
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Deubiquitinases in Ovarian Cancer: Role in Drug Resistance and Tumor Aggressiveness.

Ovarian cancer is a lethal disease due to late diagnosis and occurrence of drug resistance that limits the efficacy of platinum-based therapy. Drug resistance mechanisms include both tumor intrinsic and tumor microenvironment-related factors. A role for deubiquitinases (DUBs) is starting to emerge in ovarian cancer. DUBs are a large family of enzymes that remove ubiquitin from target proteins and participate in processes affecting drug resistance such as DNA damage repair and apoptosis. Besides, DUBs modulate the functions of T cell populations favoring an immune suppressed microenvironment. Three DUBs are proteasome-associated, whereas the large majority are not. Among the former DUBs, USP14 has been proposed to modulate transcription factors such as Bcl6 and BACH1. In addition, RPN11/PSMD14 interferes with various processes including epithelial mesenchymal transition, also favored by non-proteasomal DUBs such as USP1 by acting on Snail. Besides, USP8 by stabilizing HER family receptors can confer drug resistance. Overall, DUBs appear to be druggable, with several inhibitors under development. Based on DUBs biological role, DUBs targeting appears promising in view of combination strategies involving different therapeutic approaches. Here, we summarize the relevance of DUBs in ovarian carcinoma and provide insights into future challenges for the treatment of this disease.

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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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