dc.contributor.author |
Mattiolo, Paolo |
dc.contributor.author |
Barbero-Farran A. |
dc.contributor.author |
Yuste Mateos, Víctor J. (Víctor José) |
dc.contributor.author |
Boix Torras, Jacint |
dc.contributor.author |
Ribas i Fortuny, Judit |
dc.date |
2015-02-03T17:23:08Z |
dc.date |
2015-02-03T17:23:08Z |
dc.date |
2014 |
dc.identifier |
0006-2952 |
dc.identifier |
http://hdl.handle.net/10459.1/47850 |
dc.identifier |
https://doi.org/10.1016/j.bcp.2014.08.005 |
dc.identifier.uri |
http://hdl.handle.net/10459.1/47850 |
dc.description |
2-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 |
application/pdf |
dc.language |
eng |
dc.publisher |
Elsevier |
dc.relation |
Versió postprint del document publicat a: https://doi.org/10.1016/j.bcp.2014.08.005 |
dc.relation |
Biochemical Pharmacology, 2014, vol. 91, num. 3, p. 301-311 |
dc.rights |
cc-by-nc-nd (c) Elsevier, 2014 |
dc.rights |
https://creativecommons.org/licenses/by-nc-nd/3.0/ |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Necrosis |
dc.subject |
p53 |
dc.subject |
oxidative stress |
dc.subject |
pifithrin-mu |
dc.subject |
PES (2-phenylethynesulfonamide) |
dc.subject |
Necrosi |
dc.subject |
Estrès oxidatiu |
dc.subject |
Necrosis |
dc.subject |
Oxidative stress |
dc.title |
2-phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53 |
dc.type |
info:eu-repo/semantics/article |
dc.type |
info:eu-repo/semantics/acceptedVersion |