文章：

拮抗MDM4抑制剂CEP-1347诱导的MDM2过表达可有效激活恶性脑肿瘤细胞中的野生型p53

Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells

原文发布日期：30 August 2023

DOI: 10.3390/cancers15174326

类型: Article

开放获取: 是

英文摘要：

The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study using CEP-1347, an inhibitor of MDM4 protein expression. The effects of CEP-1347, the genetic and/or pharmacological inhibition of MDM2, and their combination on the p53 pathway in malignant brain tumor cell lines expressing wild-type p53 were investigated by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 alone or in combination with MDM2 on inhibition were examined by dye exclusion and/or colony formation assays. The treatment of malignant brain tumor cell lines with CEP-1347 markedly increased MDM2 protein expression, while blocking CEP-1347-induced MDM2 overexpression by genetic knockdown augmented the effects of CEP-1347 on the p53 pathway and cell growth. Blocking the MDM2–p53 interaction using the small molecule MDM2 inhibitor RG7112, but not MDM2 knockdown, reduced MDM4 expression. Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2′s interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells.

摘要翻译： 

MDM4抑制剂作为重新激活人类癌症中p53功能的一种策略，其研发正受到越来越多的关注；然而，它们是否影响MDM2的功能以及它们如何与MDM2抑制剂相互作用仍不清楚。本研究通过使用MDM4蛋白表达抑制剂CEP-1347来探讨这一问题。通过RT-PCR和Western blot分析，研究了CEP-1347、MDM2的遗传和/或药理学抑制及其组合对表达野生型p53的恶性脑肿瘤细胞系中p53通路的影响。通过染料排斥和/或集落形成实验检测了CEP-1347单独或与MDM2抑制联合使用的生长抑制效果。用CEP-1347处理恶性脑肿瘤细胞系显著增加了MDM2蛋白的表达，而通过基因敲低阻断CEP-1347诱导的MDM2过表达则增强了CEP-1347对p53通路和细胞生长的作用。使用小分子MDM2抑制剂RG7112阻断MDM2-p53相互作用（而非MDM2敲低）降低了MDM4的表达。因此，RG7112与CEP-1347有效协同，降低了MDM4表达，激活了p53通路，并抑制了细胞生长。本研究结果表明，将CEP-1347诱导的MDM2过表达与选择性抑制MDM2与p53的相互作用相结合，同时保留其抑制MDM4表达的能力，是一种在野生型p53癌细胞中有效重新激活p53的新颖且合理的策略。

原文链接：

Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells