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dc.contributor.authorMattiolo, Paolo
dc.contributor.authorBarbero-Farran A.
dc.contributor.authorYuste Mateos, Víctor J. (Víctor José)
dc.contributor.authorBoix Torras, Jacint
dc.contributor.authorRibas i Fortuny, Judit
dc.date.accessioned2015-02-03T17:23:08Z
dc.date.available2015-02-03T17:23:08Z
dc.date.issued2014
dc.identifier.issn0006-2952
dc.identifier.urihttp://hdl.handle.net/10459.1/47850
dc.description.abstract2-Phenylethynesulfonamide (PES) or pifithrin-μ is a promising anticancer agent with preferential toxicity for cancer cells. The type of cell death and the molecular cascades activated by this compound are controversial. Here, we demonstrate PES elicits a caspase- and BAX/BAK-independent non-necroptotic necrotic cell death, since it is not inhibited by necrostatin-1. This process is characterized by an early generation of reactive oxygen species (ROS) resulting in p53 up-regulation. Accordingly, thiolic antioxidants protect cells from PES-induced death. Furthermore, inhibiting the natural sources of glutathione with l-buthionine-sulfoximine (BSO) strongly cooperates with PES in triggering cytotoxicity. Genetically modified p53-null or p53 knocked-down cells show resistance to PES-driven necrosis. The predominant localization of p53 in chromatin-enriched fractions added to the up-regulation of the p53-responsive gene p21, strongly suggest the involvement of a transcription-dependent p53 program. On the other hand, we report an augmented production of ROS in p53-positive cells that, added to the increased p53 content in response to PES-elicited ROS, suggests that p53 and ROS are mutually regulated in response to PES. In sum, p53 up-regulation by ROS triggers a positive feedback loop responsible of further increasing ROS production and reinforcing PES-driven non-necroptotic necrosis.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherElsevier
dc.relation.isformatofVersió postprint del document publicat a: https://doi.org/10.1016/j.bcp.2014.08.005
dc.relation.ispartofBiochemical Pharmacology, 2014, vol. 91, num. 3, p. 301-311
dc.rightscc-by-nc-nd (c) Elsevier, 2014
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subjectNecrosis
dc.subjectp53
dc.subjectoxidative stress
dc.subjectpifithrin-mu
dc.subjectPES (2-phenylethynesulfonamide)
dc.subject.classificationNecrosi
dc.subject.classificationEstrès oxidatiu
dc.subject.otherNecrosis
dc.subject.otherOxidative stress
dc.title2-phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53
dc.typeinfo:eu-repo/semantics/article
dc.identifier.idgrec021381
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.1016/j.bcp.2014.08.005


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cc-by-nc-nd (c) Elsevier, 2014
Except where otherwise noted, this item's license is described as cc-by-nc-nd (c) Elsevier, 2014