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.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Nat Commun. 2024 Jun 3;15(1):4703. doi: 10.1038/s41467-024-48364-4.
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.
核因子红细胞 2 相关因子 2（NRF2）的过度激活已被确定为多种人类癌症（包括非小细胞肺癌（NSCLC））的致癌驱动因素。然而，尽管付出了巨大的努力，目前仍然没有针对 NRF2 过度激活的特异性治疗方法。在这里，我们发现肽基脯氨酰顺反异构酶 A（PPIA）是 NRF2 蛋白稳定性所必需的。PPIA 的缺失促进了 NRF2 蛋白的降解，并阻止了 NSCLC 细胞中 NRF2 驱动的生长。在机制上，PPIA 与 NRF2 物理结合，并阻止了泛素/kelch 样 ECH 相关蛋白 1（KEAP1）与 NRF2 的结合，从而阻止了泛素介导的降解。我们的 X 射线共晶结构揭示了 PPIA 通过含有反式脯氨酸 174 的疏水性序列直接与 NRF2 结构域间连接子相互作用。我们进一步证明，一种已批准用于临床的药物环孢菌素 A（CsA）可破坏 NRF2 与 PPIA 的相互作用，诱导 NRF2 泛素化和降解。有趣的是，CsA 中断了由 NRF2/KLF5/SLC1A5 途径介导的谷氨酰胺代谢，从而抑制了 NRF2 过度激活的 NSCLC 细胞的生长。CsA 和谷氨酰胺酶抑制剂联合治疗可显著延缓 NRF2 过度激活的 NSCLC 患者来源异种移植（PDX）模型中的肿瘤进展。我们的研究表明，靶向 NRF2 蛋白稳定性是治疗 NRF2 过度激活的 NSCLC 的一种可行的治疗方法。
