Home > Articles > Published articles > Constitutive Activation of p62/Sequestosome-1-Mediated Proteaphagy Regulates Proteolysis and Impairs Cell Death in Bortezomib-Resistant Mantle Cell Lymphoma |
Date: | 2022 |
Abstract: | Protein 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. |
Grants: | Ministerio de Ciencia e Innovación CTQ2011-27874 European Commission 765445 Agencia Estatal de Investigación CEX2019-000910-S European Commission 871124 Ministerio de Economía y Competitividad PI15/00102 Instituto de Salud Carlos III PI18/01383 Ministerio de Ciencia, Innovación y Universidades SAF2017-90900-REDT |
Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Subject: | Apoptosis ; Autophagy ; Proteasome inhibitor ; TUBEs ; Ubiquitin proteome ; Verteporfin |
Published in: | Cancers, Vol. 14 Núm. 4 (Feb. 2022) , art. 923, ISSN 2072-6694 |
20 p, 24.8 MB |