title: TRAIL receptor gene editing unveils TRAIL-R1 as a master player of apoptosis induced by TRAIL and ER stress.
abstract: TRAIL induces selective tumor cell death through TRAIL-R1 and TRAIL-R2. Despite the fact that these receptors share high structural homologies, induction of apoptosis upon ER stress, cell autonomous motility and invasion have solely been described to occur through TRAIL-R2. Using the TALEN gene-editing approach, we show that TRAIL-R1 can also induce apoptosis during unresolved unfolded protein response (UPR). Likewise, TRAIL-R1 was found to co-immunoprecipitate with FADD and caspase-8 during ER stress. Its deficiency conferred resistance to apoptosis induced by thaspigargin, tunicamycin or brefeldin A. Our data also demonstrate that tumor cell motility and invasion-induced by TRAIL-R2 is not cell autonomous but induced in a TRAIL-dependant manner. TRAIL-R1, on the other hand, is unable to trigger cell migration owing to its inability to induce an increase in calcium flux. Importantly, all the isogenic cell lines generated in this study revealed that apoptosis induced TRAIL is preferentially induced by TRAIL-R1. Taken together, our results provide novel insights into the physiological functions of TRAIL-R1 and TRAIL-R2 and suggest that targeting TRAIL-R1 for anticancer therapy is likely to be more appropriate owing to its lack of pro-motile signaling capability.
authors.affiliation: INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Univ. Bourgogne Franche-Comté, Dijon, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Dufour
authors.affiliation: INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Univ. Bourgogne Franche-Comté, Dijon, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Rattier
authors.affiliation: INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Univ. Bourgogne Franche-Comté, Dijon, France.
authors.forename: Andrei Alexandru
authors.initials: AA
authors.lastname: Constantinescu
authors.affiliation: INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Univ. Bourgogne Franche-Comté, Dijon, France.|Pós-graduação emCiências da Saúde, Escola de Medicina, Pontifícia Univ. Católica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Zischler
authors.affiliation: INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Univ. Bourgogne Franche-Comté, Dijon, France.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Morlé
authors.affiliation: Laboratoire des Venins et Biomolécules Thérapeutiques LR11IPT08, Institut Pasteur de Tunis, Tunis, Tunisia.
authors.forename: Hazem
authors.initials: H
authors.lastname: Ben Mabrouk
authors.affiliation: INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Univ. Bourgogne Franche-Comté, Dijon, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Humblin
authors.affiliation: INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Univ. Bourgogne Franche-Comté, Dijon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacquemin
authors.affiliation: Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland.
authors.forename: Eva
authors.initials: E
authors.lastname: Szegezdi
authors.affiliation: Cellectis, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Delacote
authors.affiliation: Laboratoire des Venins et Biomolécules Thérapeutiques LR11IPT08, Institut Pasteur de Tunis, Tunis, Tunisia.
authors.forename: Naziha
authors.initials: N
authors.lastname: Marrakchi
authors.affiliation: Univ. de Bordeaux, CNRS, IPB, UMR 5248, CBMN, Institut Européen de Chimie et de Biologie, Pessac, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Guichard
authors.affiliation: INSERM, UMR892, CNRS 6299, Université de Nantes, Nantes, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pellat-Deceunynck
authors.affiliation: INSERM U1218, Univ. de Bordeaux, Institut Bergonié, Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vacher
authors.affiliation: CLCC Eugène Marquis, INSERM ER440 Oncogenesis, Stress & Signaling, Rennes, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Legembre
authors.affiliation: INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Univ. Bourgogne Franche-Comté, Dijon, France.|Centre Georges-François Leclerc, Dijon, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.affiliation: INSERM, UMR866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, Dijon, France.|Univ. Bourgogne Franche-Comté, Dijon, France.|Centre Georges-François Leclerc, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
chemical_list: C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: TRAIL; apoptosis; cancer; receptor; signaling