title: Patulin induces apoptosis through ROS-mediated endoplasmic reticulum stress pathway.
abstract: Patulin (PAT) is a toxic metabolite produced by several filamentous fungi of the genera of Penicillium, Aspergillus, and Byssochlamys. PAT is the most common mycotoxin found in apples and apple-based products including juice, compotes, cider, and baby food. Exposure to this mycotoxin has been reported to induce intestinal and kidney injuries. This study investigated the mechanism of PAT-induced toxicity in human colon carcinoma (HCT116) and embryonic kidney cells (HEK293). We demonstrated that PAT activated endoplasmic reticulum (ER) and unfolded protein response as evidenced by up-regulation of GRP78 and GADD34, splicing of XBP1 mRNA, and expression of the proapoptotic factor CHOP. This ER stress response was accompanied by the induction of the mitochondrial apoptotic pathway. Apoptosis occurred with ROS production, drop in mitochondrial membrane potential and caspase activation. Further, we showed that deficiency of the proapoptotic protein Bax or Bak protected cells against PAT-induced apoptosis. The treatment of cells with the ROS scavenger N-acetyl cysteine inhibits the ER stress response and prevents mitochondrial apoptosis. Collectively, our data provide new mechanistic insights in the signaling pathways of the cell death induced by PAT and demonstrate that PAT induces cytotoxicity through a ROS-dependent mechanism involving ER stress and activation of mitochondrial apoptotic pathway in human intestinal and kidney cells.
authors.affiliation: *Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia, INSERM UMR-S 1180, LabEx LERMIT, Faculty of Pharmacy, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France and Université de Versailles Saint Quentin en Yvelines, 78035 Versailles, France.
authors.forename: Manel
authors.initials: M
authors.lastname: Boussabbeh
authors.affiliation: *Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia, INSERM UMR-S 1180, LabEx LERMIT, Faculty of Pharmacy, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France and Université de Versailles Saint Quentin en Yvelines, 78035 Versailles, France.
authors.forename: Intidhar
authors.initials: I
authors.lastname: Ben Salem
authors.affiliation: *Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia, INSERM UMR-S 1180, LabEx LERMIT, Faculty of Pharmacy, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France and Université de Versailles Saint Quentin en Yvelines, 78035 Versailles, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prola
authors.affiliation: *Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia, INSERM UMR-S 1180, LabEx LERMIT, Faculty of Pharmacy, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France and Université de Versailles Saint Quentin en Yvelines, 78035 Versailles, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Guilbert
authors.affiliation: *Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia, INSERM UMR-S 1180, LabEx LERMIT, Faculty of Pharmacy, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France and Université de Versailles Saint Quentin en Yvelines, 78035 Versailles, France.
authors.forename: Hassen
authors.initials: H
authors.lastname: Bacha
authors.affiliation: *Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia, INSERM UMR-S 1180, LabEx LERMIT, Faculty of Pharmacy, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France and Université de Versailles Saint Quentin en Yvelines, 78035 Versailles, France salwaabid@yahoo.fr.
authors.forename: Salwa
authors.initials: S
authors.lastname: Abid-Essefi
authors.affiliation: *Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia, INSERM UMR-S 1180, LabEx LERMIT, Faculty of Pharmacy, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France and Université de Versailles Saint Quentin en Yvelines, 78035 Versailles, France *Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia, INSERM UMR-S 1180, LabEx LERMIT, Faculty of Pharmacy, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France and Université de Versailles Saint Quentin en Yvelines, 78035 Versailles, France *Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia, INSERM UMR-S 1180, LabEx LERMIT, Faculty of Pharmacy, Université Paris-Sud, Faculté de Pharmacie, 92296 Châtenay-Malabry, France and Université de Versailles Saint Quentin en Yvelines, 78035 Versailles, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lemaire
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects*; D010365:Patulin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D017382:Reactive Oxygen Species; D010365:Patulin; D000111:Acetylcysteine
keywords: apoptosis; endoplasmic reticulum stress; oxidative stress; patulin