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PPIA dictates NRF2 stability to promote lung cancer progression

Author

Listed:
  • Weiqiang Lu

    (East China University of Science and Technology
    East China Normal University)

  • 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
    University of 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
    Guangxi Medical University Cancer Hospital)

  • 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
    Tel Aviv University)

  • Feixiong Cheng

    (Cleveland Clinic)

  • Hongbin Ji

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jin Huang

    (East China University of Science and Technology)

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.

Suggested Citation

  • 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 & Feixion, 2024. "PPIA dictates NRF2 stability to promote lung cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48364-4
    DOI: 10.1038/s41467-024-48364-4
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    References listed on IDEAS

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    1. Karina Chan & Francis Robert & Christian Oertlin & Dana Kapeller-Libermann & Daina Avizonis & Johana Gutierrez & Abram Handly-Santana & Mikhail Doubrovin & Julia Park & Christina Schoepfer & Brandon S, 2019. "eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    2. Xiongjun Wang & Ruilong Liu & Wencheng Zhu & Huiying Chu & Hua Yu & Ping Wei & Xueyuan Wu & Hongwen Zhu & Hong Gao & Ji Liang & Guohui Li & Weiwei Yang, 2019. "UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis," Nature, Nature, vol. 571(7763), pages 127-131, July.
    3. Gina M. DeNicola & Florian A. Karreth & Timothy J. Humpton & Aarthi Gopinathan & Cong Wei & Kristopher Frese & Dipti Mangal & Kenneth H. Yu & Charles J. Yeo & Eric S. Calhoun & Francesca Scrimieri & J, 2011. "Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis," Nature, Nature, vol. 475(7354), pages 106-109, July.
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