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Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies

Systemic treatment of cancer requires tumour-selective therapies that eliminate cancer cells yet preserve healthy tissues from undesired damage. Tumoral transformation is associated with profound effects in translational reprogramming of gene expression, such that tumour-specific translational regul...

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Autores principales: Villanueva, Eneko, Navarro, Pilar, Rovira-Rigau, Maria, Sibilio, Annarita, Méndez, Raúl, Fillat, Cristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357308/
https://www.ncbi.nlm.nih.gov/pubmed/28300077
http://dx.doi.org/10.1038/ncomms14833
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author Villanueva, Eneko
Navarro, Pilar
Rovira-Rigau, Maria
Sibilio, Annarita
Méndez, Raúl
Fillat, Cristina
author_facet Villanueva, Eneko
Navarro, Pilar
Rovira-Rigau, Maria
Sibilio, Annarita
Méndez, Raúl
Fillat, Cristina
author_sort Villanueva, Eneko
collection PubMed
description Systemic treatment of cancer requires tumour-selective therapies that eliminate cancer cells yet preserve healthy tissues from undesired damage. Tumoral transformation is associated with profound effects in translational reprogramming of gene expression, such that tumour-specific translational regulation presents an attractive possibility for generating oncoselective therapies. We recently discovered that mRNA translational control by cytoplasmic polyadenylation element-binding proteins (CPEBs) is reactivated in cancer. Here we present a novel approach to restrict genetic-engineered therapies to malignant tissues based on CPEB translational regulation of target mRNAs. We demonstrate that tumour reprogramming of CPEB-mediated mRNA stability and translational regulation modulates tumour-specific expression of viral proteins. For oncolytic adenoviruses, insertion of CPE regulatory sequences in the 3′-untranslated region of the E1A gene provides oncoselectivity, with full potency in cancer cells but attenuated in normal tissues. Our results demonstrate the potential of this strategy to improve oncolytic virus design and provide a framework for exploiting CPE-regulated transgenes for therapy.
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spelling pubmed-53573082017-03-24 Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies Villanueva, Eneko Navarro, Pilar Rovira-Rigau, Maria Sibilio, Annarita Méndez, Raúl Fillat, Cristina Nat Commun Article Systemic treatment of cancer requires tumour-selective therapies that eliminate cancer cells yet preserve healthy tissues from undesired damage. Tumoral transformation is associated with profound effects in translational reprogramming of gene expression, such that tumour-specific translational regulation presents an attractive possibility for generating oncoselective therapies. We recently discovered that mRNA translational control by cytoplasmic polyadenylation element-binding proteins (CPEBs) is reactivated in cancer. Here we present a novel approach to restrict genetic-engineered therapies to malignant tissues based on CPEB translational regulation of target mRNAs. We demonstrate that tumour reprogramming of CPEB-mediated mRNA stability and translational regulation modulates tumour-specific expression of viral proteins. For oncolytic adenoviruses, insertion of CPE regulatory sequences in the 3′-untranslated region of the E1A gene provides oncoselectivity, with full potency in cancer cells but attenuated in normal tissues. Our results demonstrate the potential of this strategy to improve oncolytic virus design and provide a framework for exploiting CPE-regulated transgenes for therapy. Nature Publishing Group 2017-03-16 /pmc/articles/PMC5357308/ /pubmed/28300077 http://dx.doi.org/10.1038/ncomms14833 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Villanueva, Eneko
Navarro, Pilar
Rovira-Rigau, Maria
Sibilio, Annarita
Méndez, Raúl
Fillat, Cristina
Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies
title Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies
title_full Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies
title_fullStr Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies
title_full_unstemmed Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies
title_short Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies
title_sort translational reprogramming in tumour cells can generate oncoselectivity in viral therapies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357308/
https://www.ncbi.nlm.nih.gov/pubmed/28300077
http://dx.doi.org/10.1038/ncomms14833
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