Department of Immunology and Oncology, National Centre for Biotechnology (CNB), Spanish Research Council (CSIC), Autonomous University of Madrid, Cantoblanco, Madrid, E-28049, Spain.
Department of Immunology and Oncology, National Centre for Biotechnology (CNB), Spanish Research Council (CSIC), Autonomous University of Madrid, Cantoblanco, Madrid, E-28049, Spain; Department of Biosciences, School of Biomedical and Health Sciences, European University of Madrid, Villaviciosa de Odón, Madrid, E-28670, Spain.
Redox Biol. 2024 Sep;75:103305. doi: 10.1016/j.redox.2024.103305. Epub 2024 Aug 8.
Extensive efforts have been conducted in the search for new targetable drivers of lung squamous cell carcinoma (LUSC); to date, however, candidates remain mostly unsuccessful. One of the oncogenic pathways frequently found to be active in LUSC is NFE2L2 (NRF2 transcription factor), the levels of which are regulated by KEAP1. Mutations in NFE2L2 or KEAP1 trigger NRF2 activation, an essential protector against reactive oxygen species (ROS). We hypothesized that the frequency of NRF2 activation in LUSC (∼35 %) may reflect a sensitivity of LUSC to ROS. Results from this study reveal that whereas tumors containing active forms of NRF2 were protected, ROS induction in wild-type NFE2L2/KEAP1 LUSC cells triggered ferroptosis. The mechanism of ROS action in normal-NRF2 LUSC cells involved transient NRF2 activation, miR-126-3p/miR-126-5p upregulation, and reduction of p85β and SETD5 levels. SETD5 levels reduction triggered pentose pathway gene levels increase to toxic values. Simultaneous depletion of p85β and SETD5 triggered LUSC cell death, while p85β and SETD5 overexpression rescued survival of ROS-treated normal-NRF2 LUSC cells. This shows that the cascade involving NRF2 > miR-126-3p, miR-126-5p > p85β and SETD5 is responsible for ROS-induced cell death in normal-NRF2 LUSC. Transient ROS-induced cell death is shown in 3D spheroids, patient-derived organoids, and in xenografts of wild-type NFE2L2/KEAP1 LUSC cells, supporting the potential of acute local ROS induction as a therapeutic strategy for LUSC patients with normal-NRF2.
人们在寻找肺鳞状细胞癌（LUSC）新的可靶向驱动因素方面进行了广泛的努力；然而，迄今为止，候选药物大多仍未成功。在 LUSC 中经常发现的致癌途径之一是 NFE2L2（NRF2 转录因子），其水平受 KEAP1 调节。NFE2L2 或 KEAP1 的突变会触发 NRF2 激活，这是对抗活性氧（ROS）的重要保护机制。我们假设 LUSC 中 NRF2 激活的频率（约 35%）可能反映了 LUSC 对 ROS 的敏感性。本研究的结果表明，含有活性 NRF2 的肿瘤受到保护，而在野生型 NFE2L2/KEAP1 LUSC 细胞中诱导 ROS 会引发铁死亡。正常-NRF2 LUSC 细胞中 ROS 作用的机制涉及 NRF2 的短暂激活、miR-126-3p/miR-126-5p 的上调以及 p85β 和 SETD5 水平的降低。SETD5 水平的降低引发戊糖途径基因水平升高至毒性值。同时耗尽 p85β 和 SETD5 会触发 LUSC 细胞死亡，而 ROS 处理的正常-NRF2 LUSC 细胞中 p85β 和 SETD5 的过表达挽救了细胞的存活。这表明涉及 NRF2>miR-126-3p、miR-126-5p>p85β 和 SETD5 的级联反应负责正常-NRF2 LUSC 细胞中 ROS 诱导的细胞死亡。在 3D 球体、患者来源的类器官和野生型 NFE2L2/KEAP1 LUSC 细胞的异种移植物中均显示出短暂的 ROS 诱导的细胞死亡，这支持了急性局部 ROS 诱导作为正常-NRF2 LUSC 患者的潜在治疗策略。
