2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53
| Autor: | Jacint Boix, Victor J. Yuste, Ares Barbero-Farran, Paolo Mattiolo, Judit Ribas |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
p53
Programmed cell death Necrosis Estrès oxidatiu Antineoplastic Agents PES (2-phenylethynesulfonamide) medicine.disease_cause Biochemistry pifithrin-mu Necrotic Process medicine Humans Cytotoxicity Buthionine Sulfoximine Caspase Pharmacology chemistry.chemical_classification Sulfonamides Reactive oxygen species Cell Death biology Genes p53 HCT116 Cells Necrosi Chromatin Cell biology body regions Oxidative Stress Gene Expression Regulation chemistry Oxidative stress Caspases Cancer cell biology.protein medicine.symptom Reactive Oxygen Species human activities |
| Zdroj: | Repositorio Abierto de la UdL Universitad de Lleida Recercat. Dipósit de la Recerca de Catalunya instname |
| ISSN: | 0006-2952 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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