An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression
Abstract A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nu...
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doaj-a33b3973c63c4e3da9ba0af8d938437e2021-07-11T11:05:16ZengNature Publishing GroupCell Death and Disease2041-48892021-07-0112711010.1038/s41419-021-03934-yAn MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expressionThao Thi Thanh Nguyen0Masato Shingyoji1Michiko Hanazono2Boya Zhong3Takao Morinaga4Yuji Tada5Hideaki Shimada6Kenzo Hiroshima7Masatoshi Tagawa8Division of Pathology and Cell Therapy, Chiba Cancer Center Research InstituteDivision of Respirology, Chiba Cancer CenterDivision of Pathology and Cell Therapy, Chiba Cancer Center Research InstituteDivision of Pathology and Cell Therapy, Chiba Cancer Center Research InstituteDivision of Pathology and Cell Therapy, Chiba Cancer Center Research InstituteDepartment of Respirology, Graduate School of Medicine, Chiba UniversityDepartment of Surgery, Graduate School of Medicine, Toho UniversityDepartment of Biochemistry and Genetics, Graduate School of Medicine, Chiba UniversityDivision of Pathology and Cell Therapy, Chiba Cancer Center Research InstituteAbstract A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.https://doi.org/10.1038/s41419-021-03934-y |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thao Thi Thanh Nguyen Masato Shingyoji Michiko Hanazono Boya Zhong Takao Morinaga Yuji Tada Hideaki Shimada Kenzo Hiroshima Masatoshi Tagawa |
spellingShingle |
Thao Thi Thanh Nguyen Masato Shingyoji Michiko Hanazono Boya Zhong Takao Morinaga Yuji Tada Hideaki Shimada Kenzo Hiroshima Masatoshi Tagawa An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression Cell Death and Disease |
author_facet |
Thao Thi Thanh Nguyen Masato Shingyoji Michiko Hanazono Boya Zhong Takao Morinaga Yuji Tada Hideaki Shimada Kenzo Hiroshima Masatoshi Tagawa |
author_sort |
Thao Thi Thanh Nguyen |
title |
An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression |
title_short |
An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression |
title_full |
An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression |
title_fullStr |
An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression |
title_full_unstemmed |
An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression |
title_sort |
mdm2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking e1b55kda gene on mesothelioma with the wild-type p53 through augmenting nfi expression |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-07-01 |
description |
Abstract A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma. |
url |
https://doi.org/10.1038/s41419-021-03934-y |
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