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.
Cell DiscoveryBiochemistry, 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.