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dc.contributor.authorChicote, Javier
dc.contributor.authorYuste Mateos, Víctor J. (Víctor José)
dc.contributor.authorBoix Torras, Jacint
dc.contributor.authorRibas i Fortuny, Judit
dc.date.accessioned2020-11-06T10:18:42Z
dc.date.available2020-11-06T10:18:42Z
dc.date.issued2020-10-15
dc.identifier.issn1663-9812
dc.identifier.urihttp://hdl.handle.net/10459.1/69798
dc.description.abstractMacroautophagy (hereafter autophagy) is a multistep intracellular catabolic process with pleiotropic implications in cell fate. Attending to its activation, autophagy can be classified into inducible or constitutive. Constitutive, or basal autophagy, unfolds under nutrient-replete conditions to maintain the cellular homeostasis. Autophagy inhibitory drugs are powerful tools to interrogate the role of autophagy and its consequences on cell fate. However, 3-methyladenine and various of these compounds present an intrinsic capacity to trigger cell death, for instance the broadly-employed 3-methyladenine. To elucidate whether the inhibition of basal autophagy is causative of cell demise, we have employed several representative compounds acting at different phases of the autophagic process: initiation (SBI0206965 and MHY1485), nucleation (3-methyladenine, SAR405, Spautin-1 and Cpd18), and completion (Bafilomycin A1 and Chloroquine). These compounds inhibited the basal autophagy of MEF cultures in growing conditions. Among them, 3-methyladenine, SBI-0206965, Chloroquine, and Bafilomycin A1 triggered BAX- and/or BAK-dependent cytotoxicity and caspase activation. 3-methyladenine was the only compound to induce a consistent and abrupt decrease in cell viability across a series of ontologically unrelated human cell lines. 3-methyladenine-induced cytotoxicity was not driven by the inhibition of the AKT/mTOR axis. Autophagy-deficient Fip200−/− MEFs displayed an increased sensitivity to activate caspases and to undergo cell death in response to 3-methyladenine. The cytotoxicity induced by 3-methyladenine correlated with a massive DNA damage, as shown by γ-H2A.X. This genotoxicity was observed at 10 mM 3-methyladenine, the usual concentration to inhibit autophagy and was maximized in Fip200−/− MEFs. In sum, our results suggest that, in growing conditions, autophagy acts as a protective mechanism to diminish the intrinsic cytotoxicity of 3-methyladenine. However, when the cellular stress exerted by 3-methyladenine surpasses the protective effect of basal autophagy, caspase activation and DNA damage compromise the cell viability.
dc.description.sponsorshipThis work and its publication fee were supported by a “Retos” project (SAF2016-78657-R) from the “Ministerio de Economía, Industria y Competitividad”/Fondos FEDER (Spain), granted to JR. JR is a Serra Húnter Fellow. JC holds a Ph.D. student fellowship from University of Lleida.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherFrontiers Media
dc.relationMINECO/PN2013-2016/SAF2016-78657-R
dc.relation.isformatofReproducció del document publicat a: https://doi.org/10.3389/fphar.2020.580343
dc.relation.ispartofFrontiers In Pharmacology, 2020, vol. 11, núm. 580343
dc.rightscc-by (c) Chicote, Javier et al., 2020
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es
dc.subjectAutophagy
dc.subjectAutophagy inhibitory drug
dc.titleCell Death Triggered by the Autophagy Inhibitory Drug 3-Methyladenine in Growing Conditions Proceeds With DNA Damage
dc.typeinfo:eu-repo/semantics/article
dc.date.updated2020-11-06T10:18:43Z
dc.identifier.idgrec030556
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.3389/fphar.2020.580343


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cc-by (c) Chicote, Javier et al., 2020
Except where otherwise noted, this item's license is described as cc-by (c) Chicote, Javier et al., 2020