ArticleCancer medicine2023
The NRF2 antagonist ML385 inhibits PI3K-mTOR signaling and growth of lung squamous cell carcinoma cells.
Article in Cancer medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed, 42 citations in OpenAlex.
- Cocoa flavanols, Nrf2 activation, and oxidative stress in peripheral artery disease: mechanistic findings in muscle based on outcomes from a randomized trial.American journal of physiology. Cell physiology · 2024Trial
- Baicalin attenuates angiotensin II-induced vascular endothelial injury via targeted activation of the Nrf2 signaling pathway: Integrated computational and in vitro evidence.Molecular diversity · 2026Article
- Intranasal Curcumin and N-Acetyl l-Cysteine (NAC) Attenuates Dibutyl Phthalate (DBP)-Aggravated Airway Inflammation by Targeting Ferroptosis via Nrf-2/GPx4-SLC7A11.Environmental toxicology · 2026Article
- [Standardized Construction of Lung Cancer Organoids and Their Application Progress in the Precise Treatment of Lung Cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2026Review
- FAM111B may promote the progression of lung squamous cell carcinoma through PI3K signaling pathway.Scientific reports · 2026Article
- Context-dependent NRF2 signaling in cancer: mechanisms and precision modulation.Molecular biology reports · 2026Review
- Prognostic comparison of ablation and laser excision in a population-based cohort of stage III-IV pulmonary malignant tumors.Journal of cardiothoracic surgery · 2026Article
- Resveratrol attenuates LPS-induced oxidative stress and apoptosis in HMC3 microglial cells, partly involving NRF2-related signaling.American journal of translational research · 2026Article
- The PI3K pathway is a downstream effector of NRF2 activation in the esophagus.Translational oncology · 2026Article
- Metabolic-transcriptional rewiring by NFE2L2 promotes M2 macrophage polarization and anti-PD-L1 resistance in glioma.Cancer cell international · 2025Article
- A guide to reactive oxygen species in tumour hypoxia: measurement and therapeutic implications.Molecular oncology · 2025Review
- Double vulnerability of active-NRF2 lung squamous cell carcinoma to NRF2 and TRIM24.Molecular cancer · 2025Article
- Interplay between Nrf2 and ROS in regulating epithelial-mesenchymal transition: implications for cancer metastasis and therapy.Molecular biology reports · 2025Review
- High Circulating Platelet Count as a Risk Factor for Lung Squamous Cell Carcinoma: A Retrospective Study and Mendelian Randomization Analysis.The clinical respiratory journal · 2025Article
- Bioinformatics Identification and Experimental Validation of a Prognostic Model for the Survival of Lung Squamous Cell Carcinoma Patients.Biochemical genetics · 2025Article
- Decoding the NRF2-NOTCH Crosstalk in Lung Cancer-An Update.Antioxidants (Basel, Switzerland) · 2025Review
- Dexmedetomidine Promotes Angiogenesis After Ischemic Stroke Through the NRF2/HO-1/VEGF Pathway.Neurochemical research · 2025Article
- 3D tumor cultures for drug resistance and screening development in clinical applications.Molecular cancer · 2025Review
- The molecular determinants regulating redox signaling in diabetic endothelial cells.Frontiers in pharmacology · 2025Review
- The Role of Redox Environment in Tumors.Current medicinal chemistry · 2025Review
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundLung squamous cell carcinoma (LUSC) currently has limited therapeutic options because of the relatively few validated targets and the lack of clinical drugs for some of these targets. Although NRF2/NFE2L2 pathway activation commonly occurs in LUSC, NRF2 has predominantly been studied in other cancer models. Here, we investigated the function of NRF2 in LUSC, including in organoid models, and we explored the activity of a small molecule NRF2 inhibitor ML385, which has not previously been investigated in LUSC.
methodsWe first explored the role of NRF2 signaling in LUSC cancer cell line and organoid proliferation through NRF2 knockdown or ML385 treatment, both in vivo and in vitro. Next, we performed Western blot and immunofluorescence assays to determine the effect of NRF2 inhibition on PI3K-mTOR signaling. Finally, we used cell viability and clonogenic assays to explore whether ML385 could sensitize LUSC cancer cells to PI3K inhibitors.
resultsWe find that downregulation of NRF2 signaling inhibited proliferation of LUSC cancer cell lines and organoids, both in vivo and in vitro. We also demonstrate that inhibition of NRF2 reduces PI3K-mTOR signaling, with two potential mechanisms being involved. Although NRF2 promotes AKT phosphorylation, it also acts downstream of AKT to increase RagD protein expression and recruitment of mTOR to lysosomes after amino acid stimulation. We also find that ML385 potentiates LUSC growth inhibition by a pan-PI3K inhibitor, which correlates with stronger inhibition of PI3K-mTOR signaling.
conclusionsOur data provide additional support for NRF2 promoting LUSC growth through PI3K-mTOR activation and support development of NRF2 inhibitors for the treatment of LUSC.
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