title: Cell death induced by 2-phenylethynesulfonamide uncovers a pro-survival function of BAX.
abstract: PES (2-phenylethynesulfonamide) was initially identified as an inhibitor of p53 translocation to mitochondria and named Pifithrin-µ. Further studies showed that PES selectively killed tumour cells and was thus a promising anticancer agent. PES-induced cell death was characterised by a non-apoptotic, autophagosome-rich phenotype. We observed this phenotype via electron microscopy in wild type (wt) and double Bax-/- Bak-/- (DKO) mouse embryonic fibroblasts (MEFs) treated with PES. We excluded the involvement of effector caspases, BAX and BAK, in causing PES-triggered cell death. Therefore, apoptosis was ruled out as the lethal mode of action of PES. Surprisingly, MEFs containing BAX were significantly protected from PES treatments. BAX overexpression in Bax-/- MEFs confirmed this pro-survival effect. Moreover, this protective effect required the ability of BAX to localise to mitochondrial membranes. Conversely, mitochondrial fusion induced by treatment with Mdivi-1 conferred increased resistance to MEFs subjected to PES treatment. The involvement of BAX in the regulation of mitochondrial dynamics has been reported. We propose the promotion of mitochondrial fusion by BAX to be the pro-survival function attributed to BAX.
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLleida, Av. Rovira Roure 80, E-25198 Lleida, Catalunya, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mattiolo
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLleida, Av. Rovira Roure 80, E-25198 Lleida, Catalunya, Spain.
authors.forename: Ares
authors.initials: A
authors.lastname: Barbero-Farran
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLleida, Av. Rovira Roure 80, E-25198 Lleida, Catalunya, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Amigó
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLleida, Av. Rovira Roure 80, E-25198 Lleida, Catalunya, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ripamonti
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLleida, Av. Rovira Roure 80, E-25198 Lleida, Catalunya, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Ribas
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLleida, Av. Rovira Roure 80, E-25198 Lleida, Catalunya, Spain. Electronic address: jacint.boix@mex.udl.cat.
authors.forename: Jacint
authors.initials: J
authors.lastname: Boix
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D005347:Fibroblasts / Q000166:cytology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D009154:Mutation; D010641:Phenotype; D052999:Quinazolinones / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C545747:2-phenylacetylenesulfonamide; C545662:2-phenylethylenesulfonamide; C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D000970:Antineoplastic Agents; C494827:Bax protein, mouse; D052999:Quinazolinones; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D020169:Caspases
keywords: BAK; BAX; Cell death; Mdivi-1; Mitochondrial dynamics; Pifithrin-µ