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Title:
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2-phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53
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Author:
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Mattiolo, Paolo; Barbero-Farran A.; Yuste Mateos, Víctor J. (Víctor José); Boix Torras, Jacint; Ribas i Fortuny, Judit
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Notes:
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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. |
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Subject(s):
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-Necrosis
-p53
-oxidative stress
-pifithrin-mu
-PES (2-phenylethynesulfonamide)
-Necrosi
-Estrès oxidatiu
-Necrosis
-Oxidative stress |
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Rights:
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cc-by-nc-nd (c) Elsevier, 2014
https://creativecommons.org/licenses/by-nc-nd/3.0/
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Document type:
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Article
Article - Accepted version |
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Published by:
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Elsevier
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