Previous studies have demonstrated that the antitumor potential of IU1 (a pharmacological compound), which was mediated by selective inhibition of proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). However, the underlying molecular mechanisms remain elusive. It has been well established that mdm2 (Murine double minute 2) gene was amplified and/or overexpressed in a variety of human neoplasms, including cervical cancer. Furthermore, MDM2 is critical to cervical cancer development and progression. Relatively studies have reported that USP15 and USP7 stabilized MDM2 protein levels by removing its ubiquitin chain. In the current study, we studied the cell proliferation status after IU1 treatment and the USP14-MDM2 protein interaction in cervical cancer cells. This study experimentally revealed that IU1 treatment reduced MDM2 protein expression in HeLa cervical cancer cells, along with the activation of autophagy-lysosomal protein degradation and promotion of ubiquitin-proteasome system (UPS) function, thereby blocked G0/G1 to S phase transition, decreased cell growth and triggered cell apoptosis. Thus, these results indicate that IU1 treatment simultaneously targets two major intracellular protein degradation systems, ubiquitin-proteasome and autophagy-lysosome systems, which leads to MDM2 degradation and contributes to the antitumor effect of IU1.

中文翻译：

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IU1通过MDM2降解抑制宫颈癌细胞增殖

先前的研究表明，IU1（一种药理化合物）的抗肿瘤潜力是通过选择性抑制蛋白酶体相关的去泛素酶泛素特异性蛋白酶 14（USP14）介导的。然而，潜在的分子机制仍然难以捉摸。已经确定mdm2(Murine double minute 2) 基因在包括宫颈癌在内的多种人类肿瘤中被扩增和/或过表达。此外，MDM2 对宫颈癌的发展和进展至关重要。相关研究报告称，USP15 和 USP7 通过去除其泛素链来稳定 MDM2 蛋白水平。在目前的研究中，我们研究了 IU1 治疗后的细胞增殖状态和宫颈癌细胞中 USP14-MDM2 蛋白的相互作用。本研究通过实验表明，IU1 治疗可降低 HeLa 宫颈癌细胞中 MDM2 蛋白的表达，同时激活自噬-溶酶体蛋白降解和促进泛素-蛋白酶体系统 (UPS) 功能，从而阻断 G0/G1 向 S 期转变，降低细胞生长并引发细胞凋亡。因此，