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Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells
SARS-CoV viruses have been shown to downregulate cellular events that control antiviral defenses. They adopt several strategies to silence p53, key molecule for cell homeostasis and immune control, indicating that p53 has a central role in controlling their proliferation in the host. Specific action...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9792496/ https://www.ncbi.nlm.nih.gov/pubmed/36582523 http://dx.doi.org/10.3389/fphar.2022.1018761 |
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author | Lodi, Giada Gentili, Valentina Casciano, Fabio Romani, Arianna Zauli, Giorgio Secchiero, Paola Zauli, Enrico Simioni, Carolina Beltrami, Silvia Fernandez, Mercedes Rizzo, Roberta Voltan, Rebecca |
author_facet | Lodi, Giada Gentili, Valentina Casciano, Fabio Romani, Arianna Zauli, Giorgio Secchiero, Paola Zauli, Enrico Simioni, Carolina Beltrami, Silvia Fernandez, Mercedes Rizzo, Roberta Voltan, Rebecca |
author_sort | Lodi, Giada |
collection | PubMed |
description | SARS-CoV viruses have been shown to downregulate cellular events that control antiviral defenses. They adopt several strategies to silence p53, key molecule for cell homeostasis and immune control, indicating that p53 has a central role in controlling their proliferation in the host. Specific actions are the stabilization of its inhibitor, MDM2, and the interference with its transcriptional activity. The aim of our work was to evaluate a new approach against SARS-CoV-2 by using MDM2 inhibitors to raise p53 levels and activate p53-dependent pathways, therefore leading to cell cycle inhibition. Experimental setting was performed in the alveolar basal epithelial cell line A549-hACE2, expressing high level of ACE2 receptor, to allow virus entry, as well as p53 wild-type. Cells were treated with several concentrations of Nutlin-3 or RG-7112, two known MDM2 inhibitors, for the instauration of a cell cycle block steady-state condition before and during SARS-CoV-2 infection, and for the evaluation of p53 activation and impact on virus release and related innate immune events. The results indicated an efficient cell cycle block with inhibition of the virion release and a significant inhibition of IL-6, NF-kB and IFN-λ expression. These data suggest that p53 is an efficient target for new therapies against the virus and that MDM2 inhibitors deserve to be further investigated in this field. |
format | Online Article Text |
id | pubmed-9792496 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97924962022-12-28 Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells Lodi, Giada Gentili, Valentina Casciano, Fabio Romani, Arianna Zauli, Giorgio Secchiero, Paola Zauli, Enrico Simioni, Carolina Beltrami, Silvia Fernandez, Mercedes Rizzo, Roberta Voltan, Rebecca Front Pharmacol Pharmacology SARS-CoV viruses have been shown to downregulate cellular events that control antiviral defenses. They adopt several strategies to silence p53, key molecule for cell homeostasis and immune control, indicating that p53 has a central role in controlling their proliferation in the host. Specific actions are the stabilization of its inhibitor, MDM2, and the interference with its transcriptional activity. The aim of our work was to evaluate a new approach against SARS-CoV-2 by using MDM2 inhibitors to raise p53 levels and activate p53-dependent pathways, therefore leading to cell cycle inhibition. Experimental setting was performed in the alveolar basal epithelial cell line A549-hACE2, expressing high level of ACE2 receptor, to allow virus entry, as well as p53 wild-type. Cells were treated with several concentrations of Nutlin-3 or RG-7112, two known MDM2 inhibitors, for the instauration of a cell cycle block steady-state condition before and during SARS-CoV-2 infection, and for the evaluation of p53 activation and impact on virus release and related innate immune events. The results indicated an efficient cell cycle block with inhibition of the virion release and a significant inhibition of IL-6, NF-kB and IFN-λ expression. These data suggest that p53 is an efficient target for new therapies against the virus and that MDM2 inhibitors deserve to be further investigated in this field. Frontiers Media S.A. 2022-12-13 /pmc/articles/PMC9792496/ /pubmed/36582523 http://dx.doi.org/10.3389/fphar.2022.1018761 Text en Copyright © 2022 Lodi, Gentili, Casciano, Romani, Zauli, Secchiero, Zauli, Simioni, Beltrami, Fernandez, Rizzo and Voltan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Lodi, Giada Gentili, Valentina Casciano, Fabio Romani, Arianna Zauli, Giorgio Secchiero, Paola Zauli, Enrico Simioni, Carolina Beltrami, Silvia Fernandez, Mercedes Rizzo, Roberta Voltan, Rebecca Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells |
title | Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells |
title_full | Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells |
title_fullStr | Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells |
title_full_unstemmed | Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells |
title_short | Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells |
title_sort | cell cycle block by p53 activation reduces sars-cov-2 release in infected alveolar basal epithelial a549-hace2 cells |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9792496/ https://www.ncbi.nlm.nih.gov/pubmed/36582523 http://dx.doi.org/10.3389/fphar.2022.1018761 |
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