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Updated: Jun 17, 2025
In Vivo Imaging of Reactive Oxygen Species in a Murine Wound Model
Published on: November 17, 2018
A potential therapeutic strategy based on acute oxidative stress induction for wild-type NRF2/KEAP1 lung squamous
M Sánchez-Ortega1, A Garrido2, C Cirauqui3
1Department of Immunology and Oncology, National Centre for Biotechnology (CNB), Spanish Research Council (CSIC), Autonomous University of Madrid, Cantoblanco, Madrid, E-28049, Spain.
Abstract:
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 p85βPI3K and SETD5 triggered LUSC cell death, while p85βPI3K 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 > p85βPI3K 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.
Insights
Lung squamous cell carcinoma (LUSC) with normal NFE2L2/KEAP1 genes is sensitive to reactive oxygen species (ROS). ROS induction triggers cell death via a specific molecular cascade, suggesting a potential new LUSC therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Lung squamous cell carcinoma (LUSC) has limited targetable drivers.
- The NFE2L2 (NRF2) pathway, regulated by KEAP1, is frequently active in LUSC.
- NRF2 activation protects against reactive oxygen species (ROS), but its role in LUSC sensitivity to ROS is unclear.
Purpose of the Study:
- To investigate the hypothesis that LUSC with normal NFE2L2/KEAP1 genes is sensitive to ROS.
- To elucidate the molecular mechanisms underlying ROS-induced cell death in LUSC.
- To explore the potential of ROS induction as a therapeutic strategy for LUSC.
Main Methods:
- Analysis of NRF2 activation in LUSC tumors.
- Induction of ROS in wild-type NFE2L2/KEAP1 LUSC cells and investigation of downstream effects.
- Assessment of cell death mechanisms, including ferroptosis, and molecular pathways (miR-126, p85β, SETD5) in 3D spheroids, organoids, and xenografts.
Main Results:
- LUSC tumors with active NRF2 were protected from ROS, while wild-type NFE2L2/KEAP1 LUSC cells underwent ROS-induced ferroptosis.
- ROS triggered a cascade involving transient NRF2 activation, miR-126 upregulation, and reduced p85β and SETD5 levels, leading to toxic pentose pathway activation.
- Simultaneous depletion of p85β and SETD5 induced LUSC cell death, while their overexpression rescued cell survival.
Conclusions:
- The NRF2 > miR-126 > p85β/SETD5 cascade mediates ROS-induced cell death in normal-NRF2 LUSC.
- Transient ROS induction effectively causes cell death in various LUSC models.
- Acute local ROS induction represents a promising therapeutic strategy for LUSC patients with normal NRF2.
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