7-Bromoindirubin-3'-oxime uncovers a serine protease-mediated paradigm of necrotic cell death

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dc.contributor.authorRibas i Fortuny, Judit
dc.contributor.authorYuste Mateos, Víctor J. (Víctor José)
dc.contributor.authorGarrofé Ochoa, Xènia
dc.contributor.authorMeijer, Laurent
dc.contributor.authorEsquerda Colell, Josep
dc.contributor.authorBoix Torras, Jacint
dc.date.accessioned2015-03-23T16:10:05Z
dc.date.available2015-03-23T16:10:05Z
dc.date.issued2008
dc.date.updated2015-03-23T16:10:06Z
dc.description.abstractThe new 7-bromoindirubin-3′-oxime (7BIO) compound induces caspase-independent cell death in all cell lines tested to date. Irrespective of the cell line, a 25 μM treatment for 24 h is lethal for the entire cell population. In SH-SY5Y and Jurkat cells, 7BIO (25 μM) was found to collapse the mitochondrial transmembrane potential (ΔΨm) at only 2-3 h of treatment. Concomitantly mitochondria swelled, cristae disrupted and, after 9 h, external cell membranes ruptured. In addition, endoplasmic reticulum dilated and, unexpectedly, the acute cytoplasmic destruction yielded isolated nuclei with preserved morphology and DNA integrity. Furthermore, the process was independent of both Bax and Bak, since cell viability and ΔΨm decayed indistinguishably in double Bax−/−Bak−/− mouse embryonic fibroblasts (MEFs) and their wild type counterparts. Pharmacological inhibition of the mitochondrial permeability transition pore (MPTP) did not prevent 7BIO-induced ΔΨm loss in none of the aforementioned cell lines. Caspase-independent inducers of cell death like AIF (Apoptosis Inducing Factor), cathepsins and calpains were not involved. Only the chemical inhibitors of serine proteases and, particularly, AEBSF afforded a significant protection thus suggesting a process regulated by this type of enzymes. As far as we know, these features are quite unique once taken together. Therefore, we propose 7BIO is triggering a specific type of necrotic cell death. Finally, the cytotoxicity of 7BIO on apoptosis-resistant cells like double Bax−/−Bak−/− MEFs seems of great interest envisaging cancer therapy.
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1016/j.bcp.2008.03.023
dc.identifier.idgrec012171
dc.identifier.issn0006-2952
dc.identifier.urihttp://hdl.handle.net/10459.1/48092
dc.language.isoeng
dc.publisherElsevier
dc.relation.isformatofVersió postprint del document publicat a: https://doi.org/10.1016/j.bcp.2008.03.023
dc.relation.ispartofBiochemical Pharmacology, 2008, vol. 76, num. 1, p. 39-52
dc.rights(c) Elsevier, 2008
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.subjectApoptosis
dc.subjectAutophagy
dc.subjectNecrosis
dc.subjectIndirubins
dc.subjectBcl-2
dc.subject.classificationApoptosi
dc.subject.classificationNecrosi
dc.subject.classificationAutofàgia
dc.subject.classificationMort cel·lular
dc.subject.otherApoptosis
dc.subject.otherNecrosis
dc.subject.otherAutophagy
dc.subject.otherCell death
dc.title7-Bromoindirubin-3'-oxime uncovers a serine protease-mediated paradigm of necrotic cell death
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
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