Suppressing protein damage response to overcome multidrug resistance in cancer therapy.

IF 12.5 1区 生物学 Q1 CELL BIOLOGY
Fangyuan Shao, Zongjie Li, Hao Xiao, Yujun Chen, Yuheng Zhang, Ling Li, Yuzhong Peng, Xinyi Li, Yuxing Hou, Bo Li, Xiangpeng Chu, Maoxin Ran, Dongyang Tang, Xi Han, Jiaxin Yao, Cuiting Zhang, Lijian Wang, Haifeng Li, Nan Shao, Kai Miao, Xiaoling Xu, Yanxia Shi, Changhua Zhang, Jun Yan, Ying Lin, Chu-Xia Deng
{"title":"Suppressing protein damage response to overcome multidrug resistance in cancer therapy.","authors":"Fangyuan Shao, Zongjie Li, Hao Xiao, Yujun Chen, Yuheng Zhang, Ling Li, Yuzhong Peng, Xinyi Li, Yuxing Hou, Bo Li, Xiangpeng Chu, Maoxin Ran, Dongyang Tang, Xi Han, Jiaxin Yao, Cuiting Zhang, Lijian Wang, Haifeng Li, Nan Shao, Kai Miao, Xiaoling Xu, Yanxia Shi, Changhua Zhang, Jun Yan, Ying Lin, Chu-Xia Deng","doi":"10.1038/s41421-025-00826-9","DOIUrl":null,"url":null,"abstract":"<p><p>Multidrug resistance is a significant barrier in cancer therapy largely due to poorly understood regulatory mechanisms. Here we reveal that certain anticancer drugs can bind to newly synthesized proteins prior to reaching their canonical targets, resulting in various forms of protein damage. This binding disrupts protein functions, particularly those of mitochondrial proteins, resulting in substantial cytotoxicity. The protein damage is further exacerbated by mitochondrial reactive oxygen species generated as a consequence of the initial damage, creating a positive feedback loop. In response, cancer cells rapidly initiate a chain of events, which we term the Protein Damage Response (PDR). This includes damage recognition primarily mediated by protein ubiquitination and subsequent damage clearance via the proteasome system. Notably, patients with advanced, drug-resistant metastatic breast or colon cancers exhibit elevated proteasome activity. In an effort to predict drug resistance, we developed a sensitive kit for detecting proteasome levels, enabling the identification and subtyping of patients with high proteasome activity to support tailored therapeutic strategies. Using a three-dimensional tumor slice culture-based drug sensitivity assay and an investigator-initiated clinical trial, we demonstrate that three clinically approved proteasome inhibitors effectively overcome multidrug resistance in colon and breast cancer patients with elevated proteasome activity.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"80"},"PeriodicalIF":12.5000,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484725/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Discovery","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41421-025-00826-9","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Multidrug resistance is a significant barrier in cancer therapy largely due to poorly understood regulatory mechanisms. Here we reveal that certain anticancer drugs can bind to newly synthesized proteins prior to reaching their canonical targets, resulting in various forms of protein damage. This binding disrupts protein functions, particularly those of mitochondrial proteins, resulting in substantial cytotoxicity. The protein damage is further exacerbated by mitochondrial reactive oxygen species generated as a consequence of the initial damage, creating a positive feedback loop. In response, cancer cells rapidly initiate a chain of events, which we term the Protein Damage Response (PDR). This includes damage recognition primarily mediated by protein ubiquitination and subsequent damage clearance via the proteasome system. Notably, patients with advanced, drug-resistant metastatic breast or colon cancers exhibit elevated proteasome activity. In an effort to predict drug resistance, we developed a sensitive kit for detecting proteasome levels, enabling the identification and subtyping of patients with high proteasome activity to support tailored therapeutic strategies. Using a three-dimensional tumor slice culture-based drug sensitivity assay and an investigator-initiated clinical trial, we demonstrate that three clinically approved proteasome inhibitors effectively overcome multidrug resistance in colon and breast cancer patients with elevated proteasome activity.

抑制蛋白损伤反应以克服癌症治疗中的多药耐药。
多药耐药是癌症治疗中的一个重要障碍,很大程度上是由于人们对其调控机制知之甚少。在这里,我们揭示了某些抗癌药物可以在到达其标准目标之前与新合成的蛋白质结合,从而导致各种形式的蛋白质损伤。这种结合破坏了蛋白质的功能,特别是线粒体蛋白质的功能,导致了严重的细胞毒性。由于初始损伤而产生的线粒体活性氧进一步加剧了蛋白质损伤,形成了一个正反馈循环。作为回应,癌细胞迅速启动一系列事件,我们称之为蛋白质损伤反应(PDR)。这包括主要由蛋白质泛素化介导的损伤识别和随后通过蛋白酶体系统的损伤清除。值得注意的是,晚期耐药转移性乳腺癌或结肠癌患者表现出蛋白酶体活性升高。为了预测耐药性,我们开发了一种检测蛋白酶体水平的敏感试剂盒,能够识别和分型具有高蛋白酶体活性的患者,以支持量身定制的治疗策略。通过基于三维肿瘤切片培养的药物敏感性试验和研究者发起的临床试验,我们证明了三种临床批准的蛋白酶体抑制剂有效地克服了蛋白酶体活性升高的结肠癌和乳腺癌患者的多药耐药。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信