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1. N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death

Author

Sebastien Causse, Renaud Seigneuric, Eva Szegezdi, Sarah Shirley, Guillaume Herlem, Aymeric Morlé, Tijani Gharbi, Florent Dufour, Andrei Constantinescu, Gilles Guichard, Al Batoul Zakaria, Olivier Micheau, Pascal Schneider, Gaelle Picarda, Thibault Rattier, Fabien Picaud, Guillaume Marcion, Dirk M. Zajonc, Carmen Garrido, Chris A. Benedict, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe HSPpathies (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, La Jolla Institute for Immunology [La Jolla, CA, États-Unis], Nanomédecine, imagerie, thérapeutique - UFC (EA 4662) (NIT / NANOMEDECINE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Apoptosis Research Centre [Galway, Ireland] (ARC), National University of Ireland [Galway] (NUI Galway), Universiteit Gent = Ghent University [Belgium] (UGENT), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de Biochimie, Université de Lausanne (UNIL), INCa, ARC, Ligue Nationale Contre le Cancer, Swiss National Science Foundation, National Institute of Health (AI117530 and AI101423), Conseil Regional de Bourgogne, Ministère de la recherche, ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011), ANR-07-PCVI-0031,ApoMULTI-LIB,A multivalent peptide library approach to identify functional TRAIL mimetics(2007), La Jolla Institute for Allergy & Immunology (LA JOLLA Institute), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Ghent University [Belgium] (UGENT), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), and ANR: 11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011)

Subjects
0301 basic medicine, Glycosylation, receptor, TNF, Cytomegalovirus, TRAIL, N-glycosylation, TNF-Related Apoptosis-Inducing Ligand, Mice, chemistry.chemical_compound, 0302 clinical medicine, N-linked glycosylation, carcinoma cells, Receptor, induction, Membrane Glycoproteins, Tunicamycin, apoptosis, Ligand (biochemistry), Cell biology, cancer-cells, 030220 oncology & carcinogenesis, Tumor necrosis factor alpha, signaling, Agonist, medicine.drug_class, TRAIL-R1, Cell Line, Viral Proteins, sialylation, 03 medical and health sciences, TRAIL-R2, galectin-3, medicine, Animals, Humans, DR4, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, DR5, Molecular Biology, Receptor Aggregation, Original Paper, Cell Biology, HCT116 Cells, sensitivity, Apoptosis/drug effects, Cytomegalovirus/metabolism, Membrane Glycoproteins/genetics, Membrane Glycoproteins/metabolism, Mutagenesis, Site-Directed, Nanoparticles/chemistry, Receptors, TNF-Related Apoptosis-Inducing Ligand/deficiency, Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism, Sequence Alignment, TNF-Related Apoptosis-Inducing Ligand/toxicity, Tunicamycin/toxicity, Viral Proteins/genetics, Viral Proteins/metabolism, Receptors, TNF-Related Apoptosis-Inducing Ligand, 030104 developmental biology, chemistry, human cytomegalovirus, Apoptosis, Nanoparticles, apo2l/trail
Abstract

International audience; APO2L/TRAIL (TNF-related apoptosis-inducing ligand) induces death of tumor cells through two agonist receptors, TRAIL-R1 and TRAIL-R2. We demonstrate here that N-linked glycosylation (N-glyc) plays also an important regulatory role for TRAIL-R1-mediated and mouse TRAIL receptor (mTRAIL-R)-mediated apoptosis, but not for TRAIL-R2, which is devoid of N-glycans. Cells expressing N-glyc-defective mutants of TRAIL-R1 and mouse TRAIL-R were less sensitive to TRAIL than their wild-type counterparts. Defective apoptotic signaling by N-glyc-deficient TRAIL receptors was associated with lower TRAIL receptor aggregation and reduced DISC formation, but not with reduced TRAIL-binding affinity. Our results also indicate that TRAIL receptor N-glyc impacts immune evasion strategies. The cytomegalovirus (CMV) UL141 protein, which restricts cell-surface expression of human TRAIL death receptors, binds with significant higher affinity TRAIL-R1 lacking N-glyc, suggesting that this sugar modification may have evolved as a counterstrategy to prevent receptor inhibition by UL141. Altogether our findings demonstrate that N-glyc of TRAIL-R1 promotes TRAIL signaling and restricts virus-mediated inhibition.

Published
2017
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2. TRAIL receptor gene editing unveils TRAIL-R1 as a master player of apoptosis induced by TRAIL and ER stress

Author

Carmen Garrido, Pierre Vacher, Fabien Delacote, Patrick Legembre, Gilles Guichard, Hazem Ben Mabrouk, Thibault Rattier, Olivier Micheau, Florent Dufour, Guillaume Jacquemin, Etienne Humblin, Aymeric Morlé, Eva Szegezdi, Luciana Zischler, Naziha Marrakchi, Andrei Constantinescu, Catherine Pellat-Deceunynck, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, Institut Pasteur de Tunis-Réseau International des Instituts Pasteur ( RIIP ), National University of Ireland [Galway] ( NUI Galway ), CELLECTIS, Immunologie et chimie thérapeutiques ( ICT ), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Institut Bergonié - CRLCC Bordeaux, Chemistry, Oncogenesis, Stress and Signaling ( COSS ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CRLCC Eugène Marquis ( CRLCC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLCC Eugène Marquis ( CRLCC ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), INCa SphingoDR, INCa Polynom-174, Ligue contre le cancer, CAPES BEX4938/14-3, ANR-11-LABX-0021/11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du ( 2011 ), ANR-11-IDEX-0005-02/11-LABX-0051,GR-Ex,Biogenèse et pathologies du globule rouge ( 2011 ), ANR-07-PCVI-0031,ApoMULTI-LIB,A multivalent peptide library approach to identify functional TRAIL mimetics ( 2007 ), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Pontifícia Universidade Católica do Paraná (PUCPR), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), National University of Ireland [Galway] (NUI Galway), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Bergonié [Bordeaux], UNICANCER, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-07-PCVI-0031,ApoMULTI-LIB,A multivalent peptide library approach to identify functional TRAIL mimetics(2007), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011), Micheau, Olivier, Laboratoires d'excellence - Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer - - Lipstic2011 - ANR-11-LABX-0021 - LABX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, and Physique et chimie du vivant - A multivalent peptide library approach to identify functional TRAIL mimetics - - ApoMULTI-LIB2007 - ANR-07-PCVI-0031 - PCVI - VALID

Subjects
0301 basic medicine, Time Factors, colon-cancer-cells, receptor, Fas-Associated Death Domain Protein, TRAIL, Apoptosis, Chick Embryo, Gene editing, ligand, migration, TNF-Related Apoptosis-Inducing Ligand, TALEN, Cell Movement, Tumor cell death, FADD, selective mutants, Receptor, membrane, Caspase 8, Endoplasmic Reticulum Stress, 3. Good health, Cell biology, Gene Expression Regulation, Neoplastic, Oncology, Colonic Neoplasms, Female, ER Stess, Research Paper, Signal Transduction, Breast Neoplasms, CHO Cells, TRAIL-R1, Biology, Transfection, 03 medical and health sciences, Cricetulus, death, TRAIL-R2, Calcium flux, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, cancer, Animals, Humans, metastasis, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DR4, Calcium Signaling, DR5, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, breast-cancer, Dose-Response Relationship, Drug, pathway, tumoricidal activity, Curitiba, biology.organism_classification, HCT116 Cells, Molecular biology, Signaling, Receptors, TNF-Related Apoptosis-Inducing Ligand, 030104 developmental biology, TNFRSF10B, biology.protein, Unfolded protein response, TNFRSF10A, Trail r1
Abstract

// Florent Dufour 1, 2 , Thibault Rattier 1, 2 , Andrei Alexandru Constantinescu 1, 2 , Luciana Zischler 1, 2, 3 , Aymeric Morle 1, 2 , Hazem Ben Mabrouk 4 , Etienne Humblin 1, 2 , Guillaume Jacquemin 1, 2 , Eva Szegezdi 5 , Fabien Delacote 6 , Naziha Marrakchi 4 , Gilles Guichard 7 , Catherine Pellat-Deceunynck 8 , Pierre Vacher 9 , Patrick Legembre 10 , Carmen Garrido 1, 2, 11 , Olivier Micheau 1, 2, 11 1 INSERM, UMR866, « Equipe labellisee Ligue contre le Cancer » and Laboratoire d’Excellence LipSTIC, Dijon, France 2 Univ. Bourgogne Franche-Comte, Dijon, France 3 Pos-graduacao emCiencias da Saude, Escola de Medicina, Pontificia Univ. Catolica do Parana, Curitiba, Parana, Brazil 4 Laboratoire des Venins et Biomolecules Therapeutiques LR11IPT08, Institut Pasteur de Tunis, Tunis, Tunisia 5 Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland 6 Cellectis, Paris, France 7 Univ. de Bordeaux, CNRS, IPB, UMR 5248, CBMN, Institut Europeen de Chimie et de Biologie, Pessac, France 8 INSERM, UMR892, CNRS 6299, Universite de Nantes, Nantes, France 9 INSERM U1218, Univ. de Bordeaux, Institut Bergonie, Bordeaux, France 10 CLCC Eugene Marquis, INSERM ER440 Oncogenesis, Stress & Signaling, Rennes, France 11 Centre Georges-Francois Leclerc, Dijon, France Correspondence to: Micheau Olivier, email: olivier.micheau@inserm.fr Keywords: receptor, TRAIL, signaling, apoptosis, cancer Received: September 02, 2016 Accepted: November 30, 2016 Published: December 27, 2016 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.

Published
2017
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3. Death Receptor-Induced Apoptosis Signalling Regulation by Ezrin Is Cell Type Dependent and Occurs in a DISC-Independent Manner in Colon Cancer Cells

Author

Elisabetta Iessi, Luciana Zischler, Aurélie Etringer, Marion Bergeret, Aymeric Morlé, Guillaume Jacquemin, Alexandre Morizot, Sarah Shirley, Najoua Lalaoui, Selene L Elifio-Esposito, Stefano Fais, Carmen Garrido, Eric Solary, Olivier Micheau, Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, UFR des Sciences de Santé (Université de Bourgogne), Université de Bourgogne (UB), Pós-graduação em Ciências da Saúde [Paraná, Brazil], Pontifícia Universidade Católica do Paraná, Department of Therapeutic Research and Medicines Evaluation [Rome, Italy] (Antitumor Drugs Section), Istituto Superiore di Sanità [Rome, Italy], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), CAPES (N° BEX4938/14-3), University of Bourgogne, Conseil Régional de Bourgogne, Institut National du Cancer, POLYNOM-174, Ligue Nationale contre le Cancer, ARC (Association pour la Recherche sur le Cancer), Cancéropôle Grand-Est, ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011), European Project, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Université de Bourgogne ( UB ), Department of Therapeutic Research and Medicines Evaluation [Rome, Italy] ( Antitumor Drugs Section ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Gustave Roussy ( IGR ) -Université Paris-Sud - Paris 11 ( UP11 ), ANR : Labex,LipSTIC,ANR-11-LABX-0021-01-LipSTIC, Micheau, Olivier, Laboratoires d'excellence - Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer - - Lipstic2011 - ANR-11-LABX-0021 - LABX - VALID, Apoptrain, Marie Curie RTN - INCOMING, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011), and Istituto Superiore di Sanità (ISS)

Subjects
lcsh:Medicine, Apoptosis, macromolecular substances, environment and public health, MESH: WWOX, TNF-Related Apoptosis-Inducing Ligand, MESH: TRAIL, Phosphoserine, MESH : Phosphorylation, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, fas Receptor, Phosphorylation, lcsh:Science, MESH: Ezrin, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Death Receptor, MESH : Death Receptor, MESH: Phosphorylation, Tumor Suppressor Proteins, MESH : WWOX, MESH: Apoptosis, lcsh:R, Receptors, Death Domain, MESH: Signaling, Mitochondria, MESH : Signaling, Cytoskeletal Proteins, MESH : Ezrin, MESH : TRAIL, WW Domain-Containing Oxidoreductase, MESH : PKA, Colonic Neoplasms, MESH: PKA, lcsh:Q, Oxidoreductases, MESH : Apoptosis, Signal Transduction, Research Article
Abstract

International audience; Ezrin belongs to the ERM (ezrin-radixin-moesin) protein family and has been demonstrated to regulate early steps of Fas receptor signalling in lymphoid cells, but its contribution to TRAIL-induced cell death regulation in adherent cancer cells remains unknown. In this study we report that regulation of FasL and TRAIL-induced cell death by ezrin is cell type depen-dant. Ezrin is a positive regulator of apoptosis in T-lymphoma cell line Jurkat, but a negative regulator in colon cancer cells. Using ezrin phosphorylation or actin-binding mutants, we provide evidence that negative regulation of death receptor-induced apoptosis by ezrin occurs in a cytoskeleton-and DISC-independent manner, in colon cancer cells. Remarkably, inhibition of apoptosis induced by these ligands was found to be tightly associated with regulation of ezrin phosphorylation on serine 66, the tumor suppressor gene WWOX and activation of PKA. Deficiency in WWOX expression in the liver cancer SK-HEP1 or the pancreatic Mia PaCa-2 cell lines as well as WWOX silencing or modulation of PKA activation by pharmacological regulators, in the colon cancer cell line SW480, abrogated regulation of TRAIL signalling by ezrin. Altogether our results show that death receptor pro-apoptotic signalling regulation by ezrin can occur downstream of the DISC in colon cancer cells.

Published
2015
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4. Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin's lymphoma B cells

Author

Anne Sophie Gallouet, Najoua Lalaoui, Guillaume Jacquemin, Thierry Guillaudeux, Elisabetta Iessi, Alexandre Morizot, Olivier Micheau, Aymeric Morlé, Carmen Garrido, Virginie Granci, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, This work was supported by grants of the Conseil Regional de Bourgogne, the INCa (Institut National du Cancer), Cancéropôle Grand-Est, ANR (Agence Nationale de la Recherche, ANR- 07-PCV-0031), and the European Community (ApopTrain Marie Curie RTN). GJ and VG were supported by fellowships from the Ligue Nationale contre le Cancer and the INCa., ANR-07-PCVI-0031,ApoMULTI-LIB,A multivalent peptide library approach to identify functional TRAIL mimetics(2007), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), ANR-07-PCVI-0031,PCVI,A multivalent peptide library approach to identify functional TRAIL mimetics ( 2007 ), Micheau, Olivier, Physique et chimie du vivant - A multivalent peptide library approach to identify functional TRAIL mimetics - - ApoMULTI-LIB2007 - ANR-07-PCVI-0031 - PCVI - VALID, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
p53, MESH: Signal Transduction, MESH: Cell Death, medicine.medical_treatment, Follicular lymphoma, TRAIL, Antioxidants, Inhibitor of Apoptosis Proteins, MESH : Proto-Oncogene Proteins c-bcl-2, quercetin, TNF-Related Apoptosis-Inducing Ligand, MESH : TNF-Related Apoptosis-Inducing Ligand, 0302 clinical medicine, MESH : Lymphoma, B-Cell, immune system diseases, hemic and lymphatic diseases, bax, MESH: Up-Regulation, MESH : Inhibitor of Apoptosis Proteins, Caspase 10, MESH: Tumor Suppressor Protein p53, MESH : Up-Regulation, 0303 health sciences, Cell Death, apoptosis, Hematology, MESH: Drug Resistance, Neoplasm, Mitochondria, Up-Regulation, 3. Good health, Cytokine, MESH : Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-bcl-2, caspases, 030220 oncology & carcinogenesis, MESH : Quercetin, MESH : Antioxidants, MESH : Mitochondria, MESH: Quercetin, MESH: TNF-Related Apoptosis-Inducing Ligand, Signal Transduction, Death Domain Receptor Signaling Adaptor Proteins, Programmed cell death, Lymphoma, B-Cell, MESH: Cell Line, Tumor, MESH: Mitochondria, Biology, survivin, 03 medical and health sciences, Downregulation and upregulation, follicular lymphoma, Cell Line, Tumor, Survivin, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Lymphoma, B-Cell, MESH : Signal Transduction, MESH: Caspase 10, diffused large B cell lymphoma, MESH: Humans, MESH : Cell Line, Tumor, MESH: Apoptosis, MESH : Humans, MESH: Antioxidants, MESH: Inhibitor of Apoptosis Proteins, Mcl-1, Original Articles, medicine.disease, Lymphoma, Non-Hodgkin's lymphoma, MESH : Tumor Suppressor Protein p53, proteasome, MESH: Proto-Oncogene Proteins c-bcl-2, Drug Resistance, Neoplasm, Apoptosis, MESH : Caspase 10, MESH : Cell Death, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, Tumor Suppressor Protein p53, MESH : Apoptosis, MESH : Death Domain Receptor Signaling Adaptor Proteins, MESH: Death Domain Receptor Signaling Adaptor Proteins
Abstract

International audience; BACKGROUND: Non-Hodgkin's B-cell lymphomas account for approximately 70% of B-cell lymphomas. While its incidence is dramatically increasing worldwide, the disease is still associated with high morbidity due to ineffectiveness of conventional therapies, creating an urgent need for novel therapeutic approaches. Unconventional compounds, including polyphenols and the cytokine TRAIL, are being extensively studied for their capacity to restore apoptosis in a large number of tumors, including lymphomas. DESIGN AND METHODS: Molecular mechanisms of TRAIL-resistance and reactivation of the apoptotic machinery by quercetin in non-Hodgkin's lymphoma cell lines were determined by Hoescht, flow cytometry, Western blot, qPCR, by use of siRNA or pharmacological inhibitors of the mitochondrial pathway and by immunoprecipitation followed by post-translational modification analysis. RESULTS: Results demonstrate that quercetin, a natural flavonoid, restores TRAIL-induced cell death in resistant transformed follicular lymphoma B-cell lines, despite high Bcl-2 expression levels due to the chromosomal translocation t(14;18). Quercetin rescues mitochondrial activation by inducing the proteasomal degradation of Mcl-1 and by inhibiting survivin expression at the mRNA level, irrespective of p53. Restoration of the TRAIL pathway requires Bax and Bak but is independent of enhanced TRAIL DISC formation. CONCLUSIONS: We demonstrate that inactivation of survivin and Mcl-1 expression by quercetin is sufficient to restore TRAIL sensitivity in resistant non-Hodgkin's lymphoma B cells. Our results suggest, therefore, that combining quercetin with TRAIL treatments may be useful in the treatment of non-Hodgkin's lymphoma.

Published
2012
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5. TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT

Author

Aymeric Morlé, Delphine Merino, Olivier Micheau, Bruno Robert, Elisabetta Iessi, Eric Solary, Sarah Shirley, Carmen Garrido, Najoua Lalaoui, Alexandre Morizot, Guillaume Jacquemin, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Ligue Nationale contre le Cancer, Ministère de la recherche, ARC (Association pour la Recherche sur le Cancer), INSERM et Conseil Regional de Bourgogne, Micheau, Olivier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Gustave Roussy ( IGR ) -Université Paris-Sud - Paris 11 ( UP11 ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), and Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL )

Subjects
Proliferation index, lcsh:Medicine, TNF-Related Apoptosis-Inducing Ligand, HeLa, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Molecular Cell Biology, Basic Cancer Research, Membrane Receptor Signaling, Enzyme Inhibitors, lcsh:Science, Phosphoinositide-3 Kinase Inhibitors, 0303 health sciences, Multidisciplinary, Cell Death, biology, apoptosis, 3. Good health, Cell biology, Oncology, 030220 oncology & carcinogenesis, Medicine, Female, Signal transduction, Research Article, Signal Transduction, Programmed cell death, Morpholines, proliferation, Blotting, Western, Mice, Nude, 03 medical and health sciences, TRAIL-R4, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, 030304 developmental biology, Cell growth, Akt, Cell Membrane, lcsh:R, PTEN Phosphohydrolase, Neoplasms, Experimental, biology.organism_classification, Tumor Necrosis Factor Decoy Receptors, Chromones, Apoptosis, lcsh:Q, Proto-Oncogene Proteins c-akt, HeLa Cells
Abstract

International audience; BACKGROUND: TRAIL/Apo2L is a pro-apoptotic ligand of the TNF family that engages the apoptotic machinery through two pro-apoptotic receptors, TRAIL-R1 and TRAIL-R2. This cell death program is tightly controlled by two antagonistic receptors, TRAIL-R3 and TRAIL-R4, both devoid of a functional death domain, an intracellular region of the receptor, required for the recruitment and the activation of initiator caspases. Upon TRAIL-binding, TRAIL-R4 forms a heteromeric complex with the agonistic receptor TRAIL-R2 leading to reduced caspase-8 activation and apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: We provide evidence that TRAIL-R4 can also exhibit, in a ligand independent manner, signaling properties in the cervical carcinoma cell line HeLa, through Akt. Ectopic expression of TRAIL-R4 in HeLa cells induced morphological changes, with cell rounding, loss of adherence and markedly enhanced cell proliferation in vitro and tumor growth in vivo. Disruption of the PI3K/Akt pathway using the pharmacological inhibitor LY294002, siRNA targeting the p85 regulatory subunit of phosphatidylinositol-3 kinase, or by PTEN over-expression, partially restored TRAIL-mediated apoptosis in these cells. Moreover, the Akt inhibitor, LY294002, restituted normal cell proliferation index in HeLa cells expressing TRAIL-R4. CONCLUSIONS/SIGNIFICANCE: Altogether, these results indicate that, besides its ability to directly inhibit TRAIL-induced cell death at the membrane, TRAIL-R4 can also trigger the activation of signaling pathways leading to cell survival and proliferation in HeLa cells. Our findings raise the possibility that TRAIL-R4 may contribute to cervical carcinogenesis.

Published
2011
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