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Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1

Oncolytic adenoviruses are promising new anticancer agents. To realize their full anticancer potential, they are being engineered to express therapeutic payloads. Tumor suppressor p53 function contributes to oncolytic adenovirus activity. Many cancer cells carry an intact TP53 gene but express p53 i...

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Autores principales: Vermeulen, Christie, Brachtlova, Tereza, Tol, Nikki, van der Meulen-Muileman, Ida H., Hodzic, Jasmina, van de Vrugt, Henri J., van Beusechem, Victor W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737683/
https://www.ncbi.nlm.nih.gov/pubmed/36499754
http://dx.doi.org/10.3390/ijms232315430
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author Vermeulen, Christie
Brachtlova, Tereza
Tol, Nikki
van der Meulen-Muileman, Ida H.
Hodzic, Jasmina
van de Vrugt, Henri J.
van Beusechem, Victor W.
author_facet Vermeulen, Christie
Brachtlova, Tereza
Tol, Nikki
van der Meulen-Muileman, Ida H.
Hodzic, Jasmina
van de Vrugt, Henri J.
van Beusechem, Victor W.
author_sort Vermeulen, Christie
collection PubMed
description Oncolytic adenoviruses are promising new anticancer agents. To realize their full anticancer potential, they are being engineered to express therapeutic payloads. Tumor suppressor p53 function contributes to oncolytic adenovirus activity. Many cancer cells carry an intact TP53 gene but express p53 inhibitors that compromise p53 function. Therefore, we hypothesized that oncolytic adenoviruses could be made more effective by suppressing p53 inhibitors in selected cancer cells. To investigate this concept, we attenuated the expression of the established p53 inhibitor synoviolin (SYVN1) in A549 lung cancer cells by RNA interference. Silencing SYVN1 inhibited p53 degradation, thereby increasing p53 activity, and promoted adenovirus-induced A549 cell death. Based on these observations, we constructed a new oncolytic adenovirus that expresses a short hairpin RNA against SYVN1. This virus killed A549 cells more effectively in vitro and inhibited A549 xenograft tumor growth in vivo. Surprisingly, increased susceptibility to adenovirus-mediated cell killing by SYVN1 silencing was also observed in A549 TP53 knockout cells. Hence, while the mechanism of SYVN1-mediated inhibition of adenovirus replication is not fully understood, our results clearly show that RNA interference technology can be exploited to design more potent oncolytic adenoviruses.
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spelling pubmed-97376832022-12-11 Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1 Vermeulen, Christie Brachtlova, Tereza Tol, Nikki van der Meulen-Muileman, Ida H. Hodzic, Jasmina van de Vrugt, Henri J. van Beusechem, Victor W. Int J Mol Sci Article Oncolytic adenoviruses are promising new anticancer agents. To realize their full anticancer potential, they are being engineered to express therapeutic payloads. Tumor suppressor p53 function contributes to oncolytic adenovirus activity. Many cancer cells carry an intact TP53 gene but express p53 inhibitors that compromise p53 function. Therefore, we hypothesized that oncolytic adenoviruses could be made more effective by suppressing p53 inhibitors in selected cancer cells. To investigate this concept, we attenuated the expression of the established p53 inhibitor synoviolin (SYVN1) in A549 lung cancer cells by RNA interference. Silencing SYVN1 inhibited p53 degradation, thereby increasing p53 activity, and promoted adenovirus-induced A549 cell death. Based on these observations, we constructed a new oncolytic adenovirus that expresses a short hairpin RNA against SYVN1. This virus killed A549 cells more effectively in vitro and inhibited A549 xenograft tumor growth in vivo. Surprisingly, increased susceptibility to adenovirus-mediated cell killing by SYVN1 silencing was also observed in A549 TP53 knockout cells. Hence, while the mechanism of SYVN1-mediated inhibition of adenovirus replication is not fully understood, our results clearly show that RNA interference technology can be exploited to design more potent oncolytic adenoviruses. MDPI 2022-12-06 /pmc/articles/PMC9737683/ /pubmed/36499754 http://dx.doi.org/10.3390/ijms232315430 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vermeulen, Christie
Brachtlova, Tereza
Tol, Nikki
van der Meulen-Muileman, Ida H.
Hodzic, Jasmina
van de Vrugt, Henri J.
van Beusechem, Victor W.
Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1
title Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1
title_full Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1
title_fullStr Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1
title_full_unstemmed Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1
title_short Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1
title_sort evaluation of a novel oncolytic adenovirus silencing syvn1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737683/
https://www.ncbi.nlm.nih.gov/pubmed/36499754
http://dx.doi.org/10.3390/ijms232315430
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