Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.
Research Institute of Biomedical Engineering and Department of Cell Biology, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea.
Int J Mol Sci. 2023 Aug 15;24(16):12816. doi: 10.3390/ijms241612816.
Ubiquitin-specific protease 2 (USP2) is a deubiquitinase belonging to the USPs subfamily. USP2 has been known to display various biological effects including tumorigenesis and inflammation. Therefore, we aimed to examine the sensitization effect of USP2 in TRAIL-mediated apoptosis. The pharmacological inhibitor (ML364) and siRNA targeting enhanced TNF-related apoptosis-inducing ligand (TRAIL)-induced cancer cell death, but not normal cells. Mechanistically, USP2 interacted with survivin, and ML364 degraded survivin protein expression by increasing the ubiquitination of survivin. Overexpression of survivin or USP2 significantly prevented apoptosis through cotreatment with ML364 and TRAIL, whereas a knockdown of increased sensitivity to TRAIL. Taken together, our data suggested that ML364 ubiquitylates and degrades survivin, thereby increasing the reactivity to TRAIL-mediated apoptosis in cancer cells.
泛素特异性蛋白酶 2（USP2）是一种去泛素化酶，属于 USP 亚家族。USP2 具有多种生物学效应，包括肿瘤发生和炎症。因此，我们旨在研究 USP2 在 TRAIL 介导的细胞凋亡中的敏化作用。药理学抑制剂（ML364）和针对 USP2 的 siRNA 增强了 TNF 相关凋亡诱导配体（TRAIL）诱导的癌细胞死亡，但对正常细胞没有作用。从机制上讲，USP2 与 survivin 相互作用，而 ML364 通过增加 survivin 的泛素化来降解 survivin 蛋白表达。过表达 survivin 或 USP2 可显著阻止细胞凋亡，而 cotreatment 用 ML364 和 TRAIL 处理可增加细胞对 TRAIL 的敏感性。综上所述，我们的数据表明 ML364 泛素化和降解 survivin，从而增加了癌细胞对 TRAIL 介导的细胞凋亡的反应性。
