PPIA dictates NRF2 stability to promote lung cancer progression

Weiqiang Lu (), Jiayan Cui, Wanyan Wang, Qian Hu, Yun Xue, Xi Liu, Ting Gong, Yiping Lu, Hui Ma, Xinyu Yang, Bo Feng, Qi Wang, Naixia Zhang, Yechun Xu, Mingyao Liu, Ruth Nussinov, Feixiong Cheng, Hongbin Ji and Jin Huang ()
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Weiqiang Lu: East China University of Science and Technology
Jiayan Cui: East China University of Science and Technology
Wanyan Wang: East China University of Science and Technology
Qian Hu: East China University of Science and Technology
Yun Xue: Chinese Academy of Sciences
Xi Liu: East China University of Science and Technology
Ting Gong: East China University of Science and Technology
Yiping Lu: East China University of Science and Technology
Hui Ma: East China University of Science and Technology
Xinyu Yang: East China Normal University
Bo Feng: Shanghai Jiao Tong University School of Medicine
Qi Wang: Ministry of Education
Naixia Zhang: Chinese Academy of Sciences
Yechun Xu: Chinese Academy of Sciences
Mingyao Liu: East China Normal University
Ruth Nussinov: National Cancer Institute at Frederick
Feixiong Cheng: Cleveland Clinic
Hongbin Ji: Chinese Academy of Sciences
Jin Huang: East China University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48364-4

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