A PROTAC-Based Cuproptosis Sensitizer in Lung Cancer Therapy.

IF 27.4 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Yu Wang, Xiaoyang Yao, Yingying Lu, Juan Ruan, Zhao Yang, Chunhui Wang, Niantong Yang, Yan Gao, Shuo Shi
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Abstract

As an autonomous form of regulated cell death, cuproptosis depends on copper (Cu) and mitochondrial metabolism. However, the principle metabolic pathway known as glycolysis (Warburg effect) and high glutathione (GSH) levels of tumor cells inevitably lead to suboptimal efficacy in cuproptosis. Hence, depleting the endogenous GSH within tumors and shifting from glycolysis to mitochondrial respiration are crucial factors for augmenting cuproptosis. In this study, a proteolysis targeting chimera (PROTAC)-based cuproptosis sensitizer (CuS-MD@CS) is innovatively constructed, which not only can induce cuproptosis and reactive oxygen species production via copper ions but also can regulate the expression of p53 protein via PROTACs through the ubiquitin-proteasome system in tumor cells, thus achieving endogenous GSH depletion and a shift from glycolysis to mitochondrial respiration, making cancer cells more sensitive to cuproptosis. Importantly, in vitro and in vivo experiments have verified that CuS-MD@CS effectively targets A549 cells and suppresses tumor growth through cuproptosis and apoptosis, exhibiting promising therapeutic responses. The novel PROTAC-based cuproptosis sensitizer CuS-MD@CS provides a new strategy for sensitizing cuproptosis and offers new hope for effective lung cancer treatment.

Abstract Image

一种以protac为基础的铜增生增敏剂在肺癌治疗中的应用。
作为一种受调控的细胞死亡的自主形式,铜细胞凋亡依赖于铜(Cu)和线粒体代谢。然而,主要的代谢途径被称为糖酵解(Warburg效应)和肿瘤细胞的高谷胱甘肽(GSH)水平不可避免地导致cupropsis的效果不理想。因此,消耗肿瘤内的内源性谷胱甘肽和从糖酵解转向线粒体呼吸是增加铜增生的关键因素。本研究创新性构建了一种基于蛋白水解靶向嵌合体(proteolysis targeting chimera, PROTAC)的铜变形敏化剂(CuS-MD@CS),该敏化剂不仅可以通过铜离子诱导铜变形和活性氧产生,还可以通过泛素-蛋白酶体系统通过PROTAC调节肿瘤细胞中p53蛋白的表达,从而实现内源性GSH耗损,由糖酵解向线粒体呼吸转变,使癌细胞对铜变形更加敏感。重要的是,体外和体内实验已经证实CuS-MD@CS有效靶向A549细胞,并通过cuprotosis和凋亡抑制肿瘤生长,显示出良好的治疗效果。新型protac铜凸增敏剂CuS-MD@CS为铜凸增敏提供了新的策略,为肺癌有效治疗提供了新的希望。
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
Advanced Materials
Advanced Materials 工程技术-材料科学:综合
CiteScore
43.00
自引率
4.10%
发文量
2182
审稿时长
2 months
期刊介绍: Advanced Materials, one of the world's most prestigious journals and the foundation of the Advanced portfolio, is the home of choice for best-in-class materials science for more than 30 years. Following this fast-growing and interdisciplinary field, we are considering and publishing the most important discoveries on any and all materials from materials scientists, chemists, physicists, engineers as well as health and life scientists and bringing you the latest results and trends in modern materials-related research every week.
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