靶向USP2的药理学作用通过增强细胞凋亡和铁死亡来抑制卵巢癌生长。

Pharmacological USP2 targeting suppresses ovarian cancer growth by potentiating apoptosis and ferroptosis.

作者信息

Yang Dian, Liu Xiuxiu, Yang Yinghui, Long Yu, Nan Ding, Shi Bo, Wang Jinhao, Yang Mei, Cong Haotian, Xing Lin, Zhou Feixue, Yuan Qianhui, Ta Na, Zhang Yingqiu, Ma Ruilan, Liu Fang, Liu Shuyan

机构信息

Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.

Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; Department of Gynecology, Zhongshan Hospital of Dalian University, Dalian, China.

出版信息

Arch Biochem Biophys. 2024 Dec;762:110193. doi: 10.1016/j.abb.2024.110193. Epub 2024 Oct 30.

DOI:10.1016/j.abb.2024.110193

PMID:39486565

Abstract

Ovarian cancer is a frequently observed type of gynaecologic malignancy generally associated with poor prognosis around the world. Ubiquitin-specific proteases (USPs) form the largest subfamily of deubiquitylating enzymes and have emerged as potential therapeutic targets against human cancers. Through a systematic analysis of the prognostic significance of USP expression, USP2 was found to be inversely correlated with patient survival in ovarian cancer. Accordingly, we investigated the effects of pharmacological inhibition of USP2 on ovarian cancer by exploiting its small molecule inhibitor ML364. Our findings show that ML364 effectively hindered ovarian cancer growth and migration using a series of in vitro assays. In addition to apoptosis induction, ML364 also sensitized ovarian cancer cells to ferroptosis. Mechanistically, ML364 treatment resulted in cyclin D1 downregulation, increased poly (ADP-ribose) polymerase (PARP) cleavage, and elevated ROS levels in ovarian cancer cells. Collectively, our findings suggest USP2 as a potential therapeutic target in ovarian cancer, and hence, its pharmacological inhibition warrants further investigation.

摘要

卵巢癌是一种常见的妇科恶性肿瘤，在全球范围内通常与预后不良相关。泛素特异性蛋白酶（USPs）构成去泛素化酶的最大亚家族，并已成为针对人类癌症的潜在治疗靶点。通过对USP表达的预后意义进行系统分析，发现USP2与卵巢癌患者的生存率呈负相关。因此，我们利用其小分子抑制剂ML364研究了USP2的药理学抑制对卵巢癌的影响。我们的研究结果表明，ML364通过一系列体外试验有效地抑制了卵巢癌的生长和迁移。除了诱导凋亡外，ML364还使卵巢癌细胞对铁死亡敏感。从机制上讲，ML364处理导致卵巢癌细胞中细胞周期蛋白D1下调、聚（ADP-核糖）聚合酶（PARP）裂解增加以及活性氧水平升高。总的来说，我们的研究结果表明USP2是卵巢癌的一个潜在治疗靶点，因此，对其进行药理学抑制值得进一步研究。