Oncolytic adenovirus Delta-24-RGD induces a widespread glioma proteotype remodeling during autophagy

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dc.contributor.authorGonzález Morales, Andrea
dc.contributor.authorZabaleta, Aintzane
dc.contributor.authorGarcía Moure, Marc
dc.contributor.authorAlonso Roldán, Marta
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.funderGobierno de Navarra / Nafarroako Gobernuaes
dc.contributor.funderUniversidad Pública de Navarra / Nafarroako Unibertsitate Publikoaes
dc.date.accessioned2019-08-14T11:21:27Z
dc.date.available2020-03-01T00:00:09Z
dc.date.issued2018
dc.description.abstractAdenovirus Delta-24-RGD has shown a remarkable efficacy in a phase I clinical trial for glioblastoma. Delta-24-RGD induces autophagy in glioma cells, however, the molecular derangements associated with Delta-24-RGD infection remains poorly understood. Here, proteomics was applied to characterize the glioma metabolic disturbances soon after Delta-24-RGD internalization and late in infection. Minutes post-infection, a rapid survival reprogramming of glioma cells was evidenced by an early c-Jun activation and a time-dependent dephosphorylation of multiple survival kinases. At 48 h post-infection (hpi), a severe intracellular proteostasis impairment was characterized, detecting differentially expressed proteins related to mRNA splicing, cytoskeletal organization, oxidative response, and inflammation. Specific kinase-regulated protein interactomes for Delta-24-RGD-modulated proteome revealed interferences with the activation dynamics of protein kinases C and A (PKC, PKA), tyrosine-protein kinase Src (c-Src), glycogen synthase kinase-3 (GSK-3) as well as serine/threonine-protein phosphatases 1 and 2A (PP1, PP2A) at 48hpi, in parallel with adenoviral protein overproduction. Moreover, the late activation of the nuclear factor kappa B (NF-κB) correlates with the extracellular increment of specific cytokines involved in migration, and activation of different inflammatory cells. Taken together, our integrative analysis provides further insights into the effects triggered by Delta-24-RGD in the modulation of tumor suppression and immune response against glioma. Significance: The current study provides new insights regarding the molecular mechanisms governing the glioma metabolism during Delta-24-RGD oncolytic adenoviral therapy. The compilation and analysis of intracellular and extracellular proteomics have led us to characterize: i) the cell survival reprogramming during Delta-24-RGD internalization, ii) the proteostatic disarrangement induced by Delta-24-RGD during the autophagic stage, iii) the protein interactomes for Delta-24-RGD-modulated proteome, iv) the regulatory effects on kinase dynamics induced by Delta-24-RGD late in infection, and v) the overproduction of multitasking cytokines upon Delta-24-RGD treatment. We consider that the quantitative molecular maps generated in this study may establish the foundations for the development of complementary adenoviral based-vectors to increase the potency against glioma.en
dc.description.sponsorshipThis work was funded by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (Ref. SAF2014-59340-R To ES), the Department of Economic Development from Government of Navarra (Ref. PC023-PC024, PC025, PC081-82 and PI059 to ES and PI031 to JFI), the Instituto de Salud Carlos III and Fondos Feder Europeos (PI16/00066 to MMA), the Spanish Ministry of Science and Innovation (IEDI-2015-00638 to MMA), the Department of Health of the Government of Navarra (to MMA), the Basque Foundation for Health Research (BIOEF, BIO13/CI/005 to MMA), Asociación Pablo Ugarte-Fuerza, Julen (to MMA). AGM was supported by PEJ-2014-A-61949 (MINECO), and a pre-doctoral fellowship from Public University of Navarra (UPNA). The Proteomics Unit of Navarrabiomed is a member of Proteored, PRB3-ISCIII, and is supported by grant PT17/0019/0009, of the PE I+D+I 2013-2016 funded by ISCIII and FEDER.en
dc.embargo.lift2020-03-01
dc.embargo.terms2020-03-01
dc.format.extent30 p.
dc.format.mimetypeapplication/pdfen
dc.format.mimetypeapplication/zipen
dc.identifier.doi10.1016/j.jprot.2018.11.020
dc.identifier.issn1874-3919
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/34340
dc.language.isoengen
dc.publisherElsevieren
dc.relation.ispartofJournal of Proteomics, 194 (2019) 168-178en
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2014-59340-R/ES/
dc.relation.publisherversionhttps://doi.org/10.1016/j.jprot.2018.11.020
dc.rights© 2018 Elsevier B.V. This manuscript version is made available under the CC-BY-NC-ND 4.0.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAdenovirusen
dc.subjectDelta-24RGD infectionen
dc.subjectGliomaen
dc.subjectNetworksen
dc.subjectProteomicsen
dc.subjectSignalingen
dc.titleOncolytic adenovirus Delta-24-RGD induces a widespread glioma proteotype remodeling during autophagyen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dspace.entity.typePublication
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relation.isAuthorOfPublicatione68fa53e-9888-491f-88fe-8c64434f1f6a
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication.latestForDiscoveryf93389fa-a4b1-4d45-a7c9-ef569248a409

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