title: Activation of ER stress and apoptosis by α- and β-zearalenol in HCT116 cells, protective role of Quercetin.
abstract: Zearalenone (ZEN) and its metabolites are found in many food products and are known to induce many toxic effects. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). The mechanisms by which they mediate their cytotoxic effects are not well known and seem to differ depending on the type of cells. We investigated the possible underlying mechanism in α-ZOL and β-ZOL-induced toxicity in HCT116 cells. We showed that cell treatment with α-ZOL/β-ZOL generated endoplasmic reticulum (ER) stress and activated the Unfolded Protein Response (UPR) as evidenced by XBP1 mRNA splicing and up-regulation of GADD34, GRP78, ATF4 and CHOP. Apoptosis was triggered by ZEN metabolites-induced ER stress, and executed through a mitochondria-dependent pathway, characterized by a loss of mitochondrial transmembrane potential (ΔΨm), a downstream generation of O2•(-) and caspase 3 activation. Cellular deficiency of the pro-apoptotic proteins Bax and Bak protected cells against α/β-ZOL-induced toxicity. However, treatment with α-ZOL or β-ZOL combined with Quercetin (QUER), a common dietary flavonoid with well-known antioxidant activity, significantly reduced damage induced by α and β-ZOL in all tested markers. We concluded that QUER protects against the cellular toxicity of α and β-ZOL.×.
authors.affiliation: Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia; Faculty of Sciences of Bizerte, Carthage University, Tunisia.
authors.forename: Intidhar
authors.initials: I
authors.lastname: Ben Salem
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, 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; Faculty of Sciences of Bizerte, Carthage University, Tunisia.
authors.forename: Manel
authors.initials: M
authors.lastname: Boussabbeh
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, 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. Electronic address: hassen.bacha@fmdm.rnu.tn.
authors.forename: Hassen
authors.initials: H
authors.lastname: Bacha
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France; Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Université de Versailles Saint Quentin en Yvelines, Versailles, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lemaire
authors.affiliation: Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, 5019 Monastir, Tunisia. Electronic address: salwaabid@yahoo.fr.
authors.forename: Salwa
authors.initials: S
authors.lastname: Abid-Essefi
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D015025:Zearalenone / Q000494:pharmacology*; D015029:Zeranol / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C497109:ATF4 protein, human; D000975:Antioxidants; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; C492001:HSPA9 protein, human; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C029659:zearalenol; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D015025:Zearalenone; D015029:Zeranol; D011794:Quercetin; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; C496931:PDIA6 protein, human; D019704:Protein Disulfide-Isomerases; C028226:taleranol
keywords: Apoptosis; Endoplasmic reticulum stress; Oxidative stress; Quercetin; α-Zearalenol; β-Zearalenol