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PPIA dictates NRF2 stability to promote lung cancer progression

文献类型：期刊论文

作者Lu, Weiqiang10,11,12; Cui, Jiayan12; Wang, Wanyan12; Hu, Qian12; Xue, Yun8,9; Liu, Xi12; Gong, Ting12; Lu, Yiping12; Ma, Hui12; Yang, Xinyu10,11
刊名NATURE COMMUNICATIONS
出版日期2024-06-03
卷号15期号:1页码:20
DOI10.1038/s41467-024-48364-4
通讯作者Lu, Weiqiang(wqlu@bio.ecnu.edu.cn) ; Huang, Jin(huangjin@ecust.edu.cn)
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.
WOS关键词CYCLOSPORINE-A-BINDING ; OXIDATIVE STRESS ; CELL-SURVIVAL ; CYCLOPHILIN ; PROTEIN ; GLUTAMINE ; INHIBITORS ; KEAP1 ; ACTIVATION ; MAINTAINS
资助项目National Natural Science Foundation of China (National Science Foundation of China)[81773775] ; National Natural Science Foundation of China (National Science Foundation of China)[82173857] ; National Natural Science Foundation of China (National Science Foundation of China)[82373913] ; National Natural Science Foundation of China[22S11900900] ; Shanghai Committee of Science and Technology[SKLDR-2023-KF-04] ; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism and State Key Laboratory of Drug Research ; National Facility for Protein Science in Shanghai (NFPS), Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, China
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001238270100026
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/311630]  
专题中国科学院上海药物研究所
通讯作者Lu, Weiqiang; Huang, Jin
作者单位1.Cleveland Clin, Genom Med Inst, Lerner Res Inst, Cleveland, OH USA
2.Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, Tel Aviv, Israel
3.Frederick Natl Lab Canc Res, Computat Struct Biol Sect, Basic Sci Program, Frederick, MD 21702 USA
4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China
5.Guangxi Med Univ, Canc Hosp, Nanning, Peoples R China
6.Minist Educ, Key Lab Early Prevent & Treatment Reg High Frequen, Nanning, Peoples R China
7.Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China
8.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Hangzhou, Peoples R China
9.Chinese Acad Sci, State Key Lab Cell Biol, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, Shanghai, Peoples R China
10.East China Normal Univ, Sch Life Sci, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Weiqiang,Cui, Jiayan,Wang, Wanyan,et al. PPIA dictates NRF2 stability to promote lung cancer progression[J]. NATURE COMMUNICATIONS,2024,15(1):20.
APA Lu, Weiqiang.,Cui, Jiayan.,Wang, Wanyan.,Hu, Qian.,Xue, Yun.,...&Huang, Jin.(2024).PPIA dictates NRF2 stability to promote lung cancer progression.NATURE COMMUNICATIONS,15(1),20.
MLA Lu, Weiqiang,et al."PPIA dictates NRF2 stability to promote lung cancer progression".NATURE COMMUNICATIONS 15.1(2024):20.

入库方式： OAI收割

来源：上海药物研究所

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