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PPIA dictates NRF2 stability to promote lung cancer progression.

التفاصيل البيبلوغرافية
العنوان: PPIA dictates NRF2 stability to promote lung cancer progression.
المؤلفون: Lu W; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China. wqlu@bio.ecnu.edu.cn.; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. wqlu@bio.ecnu.edu.cn., Cui J; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China., Wang W; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China., Hu Q; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China., Xue Y; State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China., Liu X; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China., Gong T; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China., Lu Y; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China., Ma H; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China., Yang X; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China., Feng B; Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wang Q; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, China.; Guangxi Medical University Cancer Hospital, Nanning, China., Zhang N; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Xu Y; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Liu M; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China., Nussinov R; Computational Structural Biology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, USA.; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Cheng F; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, USA., Ji H; State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China., Huang J; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China. huangjin@ecust.edu.cn.
المصدر: Nature communications [Nat Commun] 2024 Jun 03; Vol. 15 (1), pp. 4703. Date of Electronic Publication: 2024 Jun 03.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Carcinoma, Non-Small-Cell Lung*/metabolism , Carcinoma, Non-Small-Cell Lung*/pathology , Carcinoma, Non-Small-Cell Lung*/genetics , Kelch-Like ECH-Associated Protein 1*/metabolism , Kelch-Like ECH-Associated Protein 1*/genetics , Lung Neoplasms*/metabolism , Lung Neoplasms*/pathology , Lung Neoplasms*/genetics , NF-E2-Related Factor 2*/metabolism , Protein Stability* , Ubiquitination* , Peptidylprolyl Isomerase*/metabolism, Animals ; Female ; Humans ; Mice ; Cell Line, Tumor ; Disease Progression ; Mice, Nude ; Proteolysis
مستخلص: 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.
(© 2024. The Author(s).)
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معلومات مُعتمدة: 81972828 National Natural Science Foundation of China (National Science Foundation of China)
المشرفين على المادة: 0 (KEAP1 protein, human)
0 (Kelch-Like ECH-Associated Protein 1)
0 (NF-E2-Related Factor 2)
0 (NFE2L2 protein, human)
EC 5.2.1.8 (PPIA protein, human)
EC 5.2.1.8 (Peptidylprolyl Isomerase)
تواريخ الأحداث: Date Created: 20240603 Date Completed: 20240603 Latest Revision: 20240613
رمز التحديث: 20240613
مُعرف محوري في PubMed: PMC11148020
DOI: 10.1038/s41467-024-48364-4
PMID: 38830868
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-48364-4