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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1018761/full |
| _version_ | 1811295069202808832 |
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| author | Giada Lodi Valentina Gentili Fabio Casciano Fabio Casciano Arianna Romani Giorgio Zauli Paola Secchiero Enrico Zauli Carolina Simioni Silvia Beltrami Mercedes Fernandez Roberta Rizzo Rebecca Voltan |
| author_facet | Giada Lodi Valentina Gentili Fabio Casciano Fabio Casciano Arianna Romani Giorgio Zauli Paola Secchiero Enrico Zauli Carolina Simioni Silvia Beltrami Mercedes Fernandez Roberta Rizzo Rebecca Voltan |
| author_sort | Giada Lodi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T05:27:52Z |
| format | Article |
| id | doaj.art-aff01f04f79843be99423fa4621a001d |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T05:27:52Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-aff01f04f79843be99423fa4621a001d2022-12-22T03:00:33ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-12-011310.3389/fphar.2022.10187611018761Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cellsGiada Lodi0Valentina Gentili1Fabio Casciano2Fabio Casciano3Arianna Romani4Giorgio Zauli5Paola Secchiero6Enrico Zauli7Carolina Simioni8Silvia Beltrami9Mercedes Fernandez10Roberta Rizzo11Rebecca Voltan12Department of Environmental and Prevention Sciences and LTTA Centre, University of Ferrara, Ferrara, ItalyDepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, ItalyDepartment of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, ItalyInterdepartmental Research Center for the Study of Multiple Sclerosis and Inflammatory and Degenerative Diseases of the Nervous System, University of Ferrara, Ferrara, ItalyDepartment of Environmental and Prevention Sciences and LTTA Centre, University of Ferrara, Ferrara, ItalyResearch Department, King Khaled Eye Specialistic Hospital, Riyadh, Saudi ArabiaDepartment of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, ItalyDepartment of Translational Medicine, University of Ferrara, Ferrara, ItalyDepartment of Life Sciences and Biotechnology, University of Ferrara, Ferrara, ItalyDepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, ItalyDepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, ItalyDepartment of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, ItalyDepartment of Environmental and Prevention Sciences and LTTA Centre, University of Ferrara, Ferrara, ItalySARS-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.https://www.frontiersin.org/articles/10.3389/fphar.2022.1018761/fullnutlin-3MDM2SARS-CoV-2cell cycleIL-6p53 |
| spellingShingle | Giada Lodi Valentina Gentili Fabio Casciano Fabio Casciano Arianna Romani Giorgio Zauli Paola Secchiero Enrico Zauli Carolina Simioni Silvia Beltrami Mercedes Fernandez Roberta Rizzo Rebecca Voltan Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells Frontiers in Pharmacology nutlin-3 MDM2 SARS-CoV-2 cell cycle IL-6 p53 |
| 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 | nutlin-3 MDM2 SARS-CoV-2 cell cycle IL-6 p53 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1018761/full |
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