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Genome-Wide RNAi Screening Identifies Novel Pathways/Genes Involved in Oxidative Stress and Repurposable Drugs to Preserve Cystic Fibrosis Airway Epithelial Cell Integrity

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Immune-Inflammatory Processes and Gene Therapeutics Group, Genes, Disease and Therapy Program, Institut d’Investigació Biomèdica de Bellvitge—IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, Spain
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Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, 1012 WX Amsterdam, The Netherlands
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Bioinformatics Unit, Institut d’Investigació Biomèdica de Bellvitge—IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, Spain
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Author to whom correspondence should be addressed.
Academic Editor: Stanley Omaye
Antioxidants 2021, 10(12), 1936; https://doi.org/10.3390/antiox10121936
Received: 8 November 2021 / Revised: 23 November 2021 / Accepted: 27 November 2021 / Published: 2 December 2021
Recurrent infection-inflammation cycles in cystic fibrosis (CF) patients generate a highly oxidative environment, leading to progressive destruction of the airway epithelia. The identification of novel modifier genes involved in oxidative stress susceptibility in the CF airways might contribute to devise new therapeutic approaches. We performed an unbiased genome-wide RNAi screen using a randomized siRNA library to identify oxidative stress modulators in CF airway epithelial cells. We monitored changes in cell viability after a lethal dose of hydrogen peroxide. Local similarity and protein-protein interaction network analyses uncovered siRNA target genes/pathways involved in oxidative stress. Further mining against public drug databases allowed identifying and validating commercially available drugs conferring oxidative stress resistance. Accordingly, a catalog of 167 siRNAs able to confer oxidative stress resistance in CF submucosal gland cells targeted 444 host genes and multiple circuitries involved in oxidative stress. The most significant processes were related to alternative splicing and cell communication, motility, and remodeling (impacting cilia structure/function, and cell guidance complexes). Other relevant pathways included DNA repair and PI3K/AKT/mTOR signaling. The mTOR inhibitor everolimus, the α1-adrenergic receptor antagonist doxazosin, and the Syk inhibitor fostamatinib significantly increased the viability of CF submucosal gland cells under strong oxidative stress pressure. Thus, novel therapeutic strategies to preserve airway cell integrity from the harsh oxidative milieu of CF airways could stem from a deep understanding of the complex consequences of oxidative stress at the molecular level, followed by a rational repurposing of existing “protective” drugs. This approach could also prove useful to other respiratory pathologies. View Full-Text
Keywords: oxidative stress; airway epithelial cells; cystic fibrosis; RNAi screening; data mining; drug databases oxidative stress; airway epithelial cells; cystic fibrosis; RNAi screening; data mining; drug databases
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MDPI and ACS Style

Checa, J.; Martínez-González, I.; Maqueda, M.; Mosquera, J.L.; Aran, J.M. Genome-Wide RNAi Screening Identifies Novel Pathways/Genes Involved in Oxidative Stress and Repurposable Drugs to Preserve Cystic Fibrosis Airway Epithelial Cell Integrity. Antioxidants 2021, 10, 1936. https://doi.org/10.3390/antiox10121936

AMA Style

Checa J, Martínez-González I, Maqueda M, Mosquera JL, Aran JM. Genome-Wide RNAi Screening Identifies Novel Pathways/Genes Involved in Oxidative Stress and Repurposable Drugs to Preserve Cystic Fibrosis Airway Epithelial Cell Integrity. Antioxidants. 2021; 10(12):1936. https://doi.org/10.3390/antiox10121936

Chicago/Turabian Style

Checa, Javier, Itziar Martínez-González, Maria Maqueda, Jose L. Mosquera, and Josep M. Aran. 2021. "Genome-Wide RNAi Screening Identifies Novel Pathways/Genes Involved in Oxidative Stress and Repurposable Drugs to Preserve Cystic Fibrosis Airway Epithelial Cell Integrity" Antioxidants 10, no. 12: 1936. https://doi.org/10.3390/antiox10121936

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