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Constitutive Activation of p62/Sequestosome-1-Mediated Proteaphagy Regulates Proteolysis and Impairs Cell Death in Bortezomib-Resistant Mantle Cell Lymphoma

2022-02-01Artigo científico Acesso aberto
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dc.contributor.authorQuinet, Grégoire
dc.contributor.authorXolalpa, Wendy
dc.contributor.authorReyes-Garau, Diana
dc.contributor.authorProfitós-Pelejà, Núria
dc.contributor.authorAzkargorta, Mikel
dc.contributor.authorCeccato, Laurie
dc.contributor.authorGonzalez-Santamarta, Maria
dc.contributor.authorMarsal, Maria
dc.contributor.authorAndilla, Jordi
dc.contributor.authorAillet, Fabienne
dc.contributor.authorBosch, Francesc
dc.contributor.authorElortza, Felix
dc.contributor.authorLoza-Alvarez, Pablo
dc.contributor.authorSola, Brigitte
dc.contributor.authorCoux, Olivier
dc.contributor.authorMatthiesen, Rune
dc.contributor.authorMatthiesen, Rune
dc.contributor.authorRoué, Gaël
dc.contributor.authorRodriguez, Manuel S.
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.pblMDPI - Multidisciplinary Digital Publishing Institute
dc.date.accessioned2022-03-14T23:23:02Z
dc.date.available2022-03-14T23:23:02Z
dc.date.issued2022-02-01
dc.descriptionFunding Information: Funding: This work was supported at early stages by Spanish MINECO, CTQ2011–27874 grant. M.G.-S. is a fellow of the UbiCODE project funded by the EU’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 765445.
dc.description.abstractProtein ubiquitylation coordinates crucial cellular events in physiological and pathological conditions. A comparative analysis of the ubiquitin proteome from bortezomib (BTZ)-sensitive and BTZ-resistant mantle cell lymphoma (MCL) revealed an enrichment of the autophagy-lysosome system (ALS) in BTZ-resistant cells. Pharmacological inhibition of autophagy at the level of lysosome-fusion revealed a constitutive activation of proteaphagy and accumulation of proteasome subunits within autophagosomes in different MCL cell lines with acquired or natural resistance to BTZ. Inhibition of the autophagy receptor p62/SQSTM1 upon verteporfin (VTP) treatment disrupted proteaphagosome assembly, reduced co-localization of proteasome subunits with autophagy markers and negatively impacted proteasome activity. Finally, the silencing or pharmacological inhibition of p62 restored the apoptosis threshold at physiological levels in BTZ-resistant cells both in vitro and in vivo. In total, these results demonstrate for the first time a proteolytic switch from the ubiquitin-proteasome system (UPS) to ALS in B-cell lymphoma refractory to proteasome inhibition, pointing out a crucial role for proteaphagy in this phenomenon and paving the way for the design of alternative therapeutic venues in treatment-resistant tumors.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent26047138
dc.identifier.doi10.3390/cancers14040923
dc.identifier.issn2072-6694
dc.identifier.otherPURE: 42051362
dc.identifier.otherPURE UUID: 2158af6c-d910-478c-a692-040f73948d4c
dc.identifier.otherScopus: 85124958813
dc.identifier.otherWOS: 000763741100001
dc.identifier.urihttp://hdl.handle.net/10362/134490
dc.identifier.urlhttps://www.scopus.com/pages/publications/85124958813
dc.language.isoeng
dc.peerreviewedyes
dc.subjectApoptosis
dc.subjectAutophagy
dc.subjectProteasome inhibitor
dc.subjectTUBEs
dc.subjectUbiquitin proteome
dc.subjectVerteporfin
dc.subjectOncology
dc.subjectCancer Research
dc.subjectSDG 3 - Good Health and Well-being
dc.titleConstitutive Activation of p62/Sequestosome-1-Mediated Proteaphagy Regulates Proteolysis and Impairs Cell Death in Bortezomib-Resistant Mantle Cell Lymphomaen
dc.typejournal article
degois.publication.issue4
degois.publication.titleCancers
degois.publication.volume14
dspace.entity.typePublication
person.familyNameMatthiesen
person.givenNameRune
person.identifier1319342
person.identifier.ciencia-idBB1A-A606-EE77
person.identifier.orcid0000-0002-6353-2616
person.identifier.scopus-author-id9741897800
rcaap.rightsopenAccess
relation.isAuthorOfPublication67181d3c-b83e-4151-9a74-0ea14aeb7f05
relation.isAuthorOfPublication.latestForDiscovery67181d3c-b83e-4151-9a74-0ea14aeb7f05

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