文献类型：期刊文献

英文题名：PPIA dictates NRF2 stability to promote lung cancer progression

作者：Lu, Weiqiang[1,2,3];Cui, Jiayan[1];Wang, Wanyan[1];Hu, Qian[1];Xue, Yun[4,5];Liu, Xi[1];Gong, Ting[1];Lu, Yiping[1];Ma, Hui[1];Yang, Xinyu[2,3];Feng, Bo[6];Wang, Qi[7,8];Zhang, Naixia[9];Xu, Yechun[9];Liu, Mingyao[2,3];Nussinov, Ruth[10,11];Cheng, Feixiong[12];Ji, Hongbin[4,5];Huang, Jin[1]

机构：[1]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai, Peoples R China;[2]East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai, Peoples R China;[3]East China Normal Univ, Sch Life Sci, Shanghai, Peoples R China;[4]Chinese Acad Sci, State Key Lab Cell Biol, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, Shanghai, Peoples R China;[5]Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Hangzhou, Peoples R China;[6]Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China;[7]Minist Educ, Key Lab Early Prevent & Treatment Reg High Frequen, Nanning, Peoples R China;[8]Guangxi Med Univ, Canc Hosp, Nanning, Peoples R China;[9]Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China;[10]Frederick Natl Lab Canc Res, Computat Struct Biol Sect, Basic Sci Program, Frederick, MD 21702 USA;[11]Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, Tel Aviv, Israel;[12]Cleveland Clin, Genom Med Inst, Lerner Res Inst, Cleveland, OH USA

年份：2024

卷号：15

期号：1

外文期刊名：NATURE COMMUNICATIONS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001238270100026)】；

基金：This project was supported by the National Natural Science Foundation of China (81773775, H.J., 82173857, H.J., 82373913 H.J.) and Shanghai Committee of Science and Technology (22S11900900, H.J.), Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism and State Key Laboratory of Drug Research, SKLDR-2023-KF-04. We thank Prof. Kangdong Liu (Zhengzhou University) for technical assistance of PDX study. We thank Prof. Naixia Zhang (Shanghai Institute of Material Medica) for technical assistance of NMR study. We thank Prof. Hua Lu (Tulane University) for critical reading and editing of our manuscript. We thank Dr. Wenming Qin and Dr. Hai Wu at SSRF beamline BL19U for assistance with data collection. We thank the staff members of the Large-scale Protein Preparation System at the National Facility for Protein Science in Shanghai (NFPS), Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, China for providing technical support and assistance in data collection and analysis.

语种：英文

摘要：Nuclear factor erythroid 2-related factor 2 (NRF2) hyperactivation has been established as an oncogenic driver in a variety of human cancers, including non-small cell lung cancer (NSCLC). However, despite massive efforts, no specific therapy is currently available to target NRF2 hyperactivation. Here, we identify peptidylprolyl isomerase A (PPIA) is required for NRF2 protein stability. Ablation of PPIA promotes NRF2 protein degradation and blocks NRF2-driven growth in NSCLC cells. Mechanistically, PPIA physically binds to NRF2 and blocks the access of ubiquitin/Kelch Like ECH Associated Protein 1 (KEAP1) to NRF2, thus preventing ubiquitin-mediated degradation. Our X-ray co-crystal structure reveals that PPIA directly interacts with a NRF2 interdomain linker via a trans-proline 174-harboring hydrophobic sequence. We further demonstrate that an FDA-approved drug, cyclosporin A (CsA), impairs the interaction of NRF2 with PPIA, inducing NRF2 ubiquitination and degradation. Interestingly, CsA interrupts glutamine metabolism mediated by the NRF2/KLF5/SLC1A5 pathway, consequently suppressing the growth of NRF2-hyperactivated NSCLC cells. CsA and a glutaminase inhibitor combination therapy significantly retard tumor progression in NSCLC patient-derived xenograft (PDX) models with NRF2 hyperactivation. Our study demonstrates that targeting NRF2 protein stability is an actionable therapeutic approach to treat NRF2-hyperactivated NSCLC. Despite being an established oncogenic driver of non-small cell lung cancer (NSCLC), therapies targeting NRF2 hyperactivation are lacking. Here, the authors identify peptidylprolyl isomerase A (PPIA) as a mediator of NRF2 stability and demonstrate the efficacy of targeting this interaction with cyclosporin A in preclinical models of NSCLC.