MG132-mediated Suppression of the Ubiquitin-proteasome Pathway Enhances the Sensitivity of Endometrial Cancer Cells to Cisplatin.

IF 2.6 4区医学 Q3 CHEMISTRY, MEDICINAL Anti-cancer agents in medicinal chemistry Pub Date : 2024-10-01 DOI:10.2174/0118715206343550240919055701

Zhanhu Zhang, Yiqian Ding

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Abstract

Background: Tumor cell resistance to cisplatin is a common challenge in endometrial cancer chemotherapy, stemming from various mechanisms. Targeted therapies using proteasome inhibitors, such as MG132, have been investigated to enhance cisplatin sensitivity, potentially offering a novel treatment approach.

Objective: The aim of this study was to investigate the effects of MG132 on cisplatin sensitivity in the human endometrial cancer (EC) cell line RL95-2, focusing on cell proliferation, apoptosis, and cell signaling.

Methods: Human endometrial cancer RL95-2 cells were exposed to MG132, and cell viability was assessed in a dose-dependent manner. The study evaluated the effect of MG132 on cisplatin-induced proliferation inhibition and apoptosis, correlating with caspase-3 activation and reactive oxygen species (ROS) upregulation. Additionally, we examined the inhibition of the ubiquitin-proteasome system and the expression of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and IL-13 during MG132 and cisplatin co-administration.

Results: MG132 exposure significantly reduced cell viability in a dose-dependent manner. It augmented cisplatin- induced proliferation inhibition and enhanced apoptosis, correlating with caspase-3 activation and ROS upregulation. Molecular analysis revealed a profound inhibition of the ubiquitin-proteasome system. MG132 also significantly increased the expression of cisplatin-induced pro-inflammatory cytokines, suggesting a transition from chronic to acute inflammation.

Conclusion: MG132 enhances the therapeutic efficacy of cisplatin in human EC cells by suppressing the ubiquitin- proteasome pathway, reducing cell viability, enhancing apoptosis, and shifting the inflammatory response. These findings highlighted the potential of MG132 as an adjuvant in endometrial cancer chemotherapy. Further research is needed to explore detailed mechanisms and clinical applications of this combination therapy.

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MG132- 介导的泛素-蛋白酶体通路抑制增强了子宫内膜癌细胞对顺铂的敏感性

背景：肿瘤细胞对顺铂的耐药性是子宫内膜癌化疗中常见的难题，其产生机制多种多样。使用蛋白酶体抑制剂（如 MG132）的靶向疗法已被研究用于增强顺铂的敏感性，有可能提供一种新的治疗方法：方法：将人子宫内膜癌 RL95-2 细胞暴露于 MG132，以剂量依赖的方式评估细胞活力。研究评估了 MG132 对顺铂诱导的增殖抑制和细胞凋亡的影响，这与 Caspase-3 激活和活性氧（ROS）上调有关。此外，我们还检测了 MG132 和顺铂联合给药期间泛素-蛋白酶体系统的抑制作用以及促炎细胞因子 IL-1β、IL-6、IL-8 和 IL-13 的表达：结果：暴露于 MG132 会以剂量依赖的方式明显降低细胞活力。它增强了顺铂诱导的增殖抑制和细胞凋亡，与 Caspase-3 激活和 ROS 上调相关。分子分析表明，MG132 对泛素-蛋白酶体系统有很强的抑制作用。MG132 还能明显增加顺铂诱导的促炎细胞因子的表达，表明炎症从慢性向急性过渡：结论：MG132通过抑制泛素-蛋白酶体途径、降低细胞活力、增强细胞凋亡和改变炎症反应，增强了顺铂对人类EC细胞的疗效。这些发现凸显了 MG132 作为子宫内膜癌化疗辅助药物的潜力。还需要进一步的研究来探索这种联合疗法的详细机制和临床应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL

CiteScore

5.10

自引率

3.60%

发文量

323

审稿时长

4-8 weeks

期刊介绍： Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.