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Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection
Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant glioma. Oncolytic adenoviruses are being modified to exploit the aberrant expression of proteins in tumor cells to increase the antiglioma efficacy. E1A mutant adenovirus Delta-24-RGD (DNX-2401) has shown a favorable t...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089549/ https://www.ncbi.nlm.nih.gov/pubmed/30123426 http://dx.doi.org/10.18632/oncotarget.25774 |
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author | González-Morales, Andrea Zabaleta, Aintzane Guruceaga, Elizabeth Alonso, Marta M. García-Moure, Marc Fernández-Irigoyen, Joaquín Santamaría, Enrique |
author_facet | González-Morales, Andrea Zabaleta, Aintzane Guruceaga, Elizabeth Alonso, Marta M. García-Moure, Marc Fernández-Irigoyen, Joaquín Santamaría, Enrique |
author_sort | González-Morales, Andrea |
collection | PubMed |
description | Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant glioma. Oncolytic adenoviruses are being modified to exploit the aberrant expression of proteins in tumor cells to increase the antiglioma efficacy. E1A mutant adenovirus Delta-24-RGD (DNX-2401) has shown a favorable toxicity profile and remarkable efficacy in a first-in-human phase I clinical trial. However, the comprehensive modulation of glioma metabolism in response to Delta-24-RGD infection is poorly understood. Integrating mass spectrometry based-quantitative proteomics, physical and functional interaction data, and biochemical approaches, we conducted a cell-wide study of cytosolic, nuclear, and secreted glioma proteomes throughout the early time course of Delta-24-RGD infection. In addition to the severe proteostasis impairment detected during the first hours post-infection (hpi), Delta-24-RGD induces a transient inhibition of signal transducer and activator of transcription 3 (STAT3), and transcription factor AP-1 (c-JUN) between 3 and 10hpi, increasing the nuclear factor kappa B (NF-κB) activity at 6hpi. Furthermore, Delta-24-RGD specifically modulates the activation dynamics of protein kinase C (PKC), extracellular signal–regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) pathways early in infection. At extracellular level, Delta-24-RGD triggers a time –dependent dynamic production of multitasking cytokines, and chemotactic factors, suggesting potential pleiotropic effects on the immune system reactivation. Taken together, these data help us to understand the mechanisms used by Delta-24-RGD to exploit glioma proteome organization. Further mining of this proteomic resource may enable design and engineering complementary adenoviral based-vectors to increase the specificity and potency against glioma. |
format | Online Article Text |
id | pubmed-6089549 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-60895492018-08-17 Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection González-Morales, Andrea Zabaleta, Aintzane Guruceaga, Elizabeth Alonso, Marta M. García-Moure, Marc Fernández-Irigoyen, Joaquín Santamaría, Enrique Oncotarget Research Paper Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant glioma. Oncolytic adenoviruses are being modified to exploit the aberrant expression of proteins in tumor cells to increase the antiglioma efficacy. E1A mutant adenovirus Delta-24-RGD (DNX-2401) has shown a favorable toxicity profile and remarkable efficacy in a first-in-human phase I clinical trial. However, the comprehensive modulation of glioma metabolism in response to Delta-24-RGD infection is poorly understood. Integrating mass spectrometry based-quantitative proteomics, physical and functional interaction data, and biochemical approaches, we conducted a cell-wide study of cytosolic, nuclear, and secreted glioma proteomes throughout the early time course of Delta-24-RGD infection. In addition to the severe proteostasis impairment detected during the first hours post-infection (hpi), Delta-24-RGD induces a transient inhibition of signal transducer and activator of transcription 3 (STAT3), and transcription factor AP-1 (c-JUN) between 3 and 10hpi, increasing the nuclear factor kappa B (NF-κB) activity at 6hpi. Furthermore, Delta-24-RGD specifically modulates the activation dynamics of protein kinase C (PKC), extracellular signal–regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) pathways early in infection. At extracellular level, Delta-24-RGD triggers a time –dependent dynamic production of multitasking cytokines, and chemotactic factors, suggesting potential pleiotropic effects on the immune system reactivation. Taken together, these data help us to understand the mechanisms used by Delta-24-RGD to exploit glioma proteome organization. Further mining of this proteomic resource may enable design and engineering complementary adenoviral based-vectors to increase the specificity and potency against glioma. Impact Journals LLC 2018-07-24 /pmc/articles/PMC6089549/ /pubmed/30123426 http://dx.doi.org/10.18632/oncotarget.25774 Text en Copyright: © 2018 González-Morales et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper González-Morales, Andrea Zabaleta, Aintzane Guruceaga, Elizabeth Alonso, Marta M. García-Moure, Marc Fernández-Irigoyen, Joaquín Santamaría, Enrique Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection |
title | Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection |
title_full | Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection |
title_fullStr | Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection |
title_full_unstemmed | Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection |
title_short | Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection |
title_sort | spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus delta-24-rgd infection |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089549/ https://www.ncbi.nlm.nih.gov/pubmed/30123426 http://dx.doi.org/10.18632/oncotarget.25774 |
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