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1. 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, and Olivier Micheau

Subjects
Medicine, Science
Abstract

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 dependant. 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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2. Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin’s lymphoma B cells

Author

Guillaume Jacquemin, Virginie Granci, Anne Sophie Gallouet, Najoua Lalaoui, Aymeric Morlé, Elisabetta Iessi, Alexandre Morizot, Carmen Garrido, Thierry Guillaudeux, and Olivier Micheau

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

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

Author

Najoua Lalaoui, Aymeric Morlé, Delphine Mérino, Guillaume Jacquemin, Elisabetta Iessi, Alexandre Morizot, Sarah Shirley, Bruno Robert, Eric Solary, Carmen Garrido, and Olivier Micheau

Subjects
Medicine, Science
Abstract

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.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.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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4. 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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5. Immunoprecipitation of Death Inducing Signaling Complex by Caspase-8

Author

Andrei Alexandru, Constantinescu, Aymeric, Morlé, and Olivier, Micheau

Subjects
Caspase 8, Death Domain Receptor Signaling Adaptor Proteins, Fas Ligand Protein, Multiprotein Complexes, Blotting, Western, Immunoprecipitation, fas Receptor, Protein Binding
Abstract

Analysis of CD95/Fas complexes by immunoprecipitation has long relied on the monoclonal antibody APO1 or tagged recombinant Fas ligand. Immunoprecipitation is an elegant and efficient procedure to investigate endogenous protein interactions or complexes. Provided that the targeted complex is soluble in mild detergent these complexes can be recovered using protein A/G-coupled Sepharose beads and further analyzed after denaturation and electrophoretic separation by western blotting or mass spectrometry. Herein, we describe in detail the method used in our laboratory to immunoprecipitate and analyze by immunoblot complexes containing caspase-8, using a commercial antibody directed against caspase-8.

Published
2017

6. Immunoprecipitation of Death Inducing Signaling Complex by Caspase-8

Author

Aymeric Morlé, Olivier Micheau, Andrei Constantinescu, 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)-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), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-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), Springer Protocols, 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), 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, 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 ) -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 ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), and Université de Bourgogne ( UB ) -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 )

Subjects
0301 basic medicine, Electrophoresis, Immunoblots, Immunoprecipitation, medicine.drug_class, Caspase 8, Monoclonal antibody, Sepharose, 03 medical and health sciences, 0302 clinical medicine, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, biology, Chemistry, Protein extracts, Fas receptor, DISC, 3. Good health, Blot, 030104 developmental biology, Biochemistry, 030220 oncology & carcinogenesis, Death-inducing signaling complex, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Protein A, Caspase-8
Abstract

Ce chapitre est compris dans un volume de la série Methods in Molecular Biology (ISSN 1064-3745); International audience; Analysis of CD95/Fas complexes by immunoprecipitation has long relied on the monoclonal antibody APO1 or tagged recombinant Fas ligand. Immunoprecipitation is an elegant and efficient procedure to investigate endogenous protein interactions or complexes. Provided that the targeted complex is soluble in mild detergent these complexes can be recovered using protein A/G-coupled Sepharose beads and further analyzed after denaturation and electrophoretic separation by western blotting or mass spectrometry. Herein, we describe in detail the method used in our laboratory to immunoprecipitate and analyze by immunoblot complexes containing caspase-8, using a commercial antibody directed against caspase-8.

Published
2017
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7. 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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8. Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGFα

Author

Julia D. Knopf, Lina Wunderle, Colin Adrain, Kvido Strisovsky, Nathalie Kühnle, Aymeric Morlé, Beate Hehn, Marius K. Lemberg, and Matthew Freeman

Subjects
0301 basic medicine, Proteases, Intramembrane protease, Golgi Apparatus, Endoplasmic Reticulum, Exosomes, Article, 03 medical and health sciences, symbols.namesake, Mice, Animals, Secretion, Secretory pathway, TGFα, Multidisciplinary, 030102 biochemistry & molecular biology, biology, Rhomboid protease, Endoplasmic reticulum, Rhomboid, Membrane Proteins, Golgi apparatus, Transforming Growth Factor alpha, Cell biology, endoplasmic reticulum, 030104 developmental biology, RHBDL4, symbols, biology.protein, rhomboid protease
Abstract

Rhomboid intramembrane proteases are the enzymes that release active epidermal growth factor receptor (EGFR) ligands in Drosophila and C. elegans, but little is known about their functions in mammals. Here we show that the mammalian rhomboid protease RHBDL4 (also known as Rhbdd1) promotes trafficking of several membrane proteins, including the EGFR ligand TGFα, from the endoplasmic reticulum (ER) to the Golgi apparatus, thereby triggering their secretion by extracellular microvesicles. Our data also demonstrate that RHBDL4-dependent trafficking control is regulated by G-protein coupled receptors, suggesting a role for this rhomboid protease in pathological conditions, including EGFR signaling. We propose that RHBDL4 reorganizes trafficking events within the early secretory pathway in response to GPCR signaling. Our work identifies RHBDL4 as a rheostat that tunes secretion dynamics and abundance of specific membrane protein cargoes. Baden-Württemberg Stiftung; Network of Aging Research (NAR, University of Heidelberg); Deutsche Forschungsgemeinschaft grant: (SFB 1036, TP 12); EMBO Installation Grant number: (2329); Ministry of Education, Youth and Sports of the Czech Republic projects: (LK11206, LO1302); Medical Research Council programme number: (U105178780); Boehringer-Ingelheim.

Published
2016

9. Hyperthermia restores apoptosis induced by death receptors through aggregation-induced c-FLIP cytosolic depletion

Author

Aymeric, Morlé, Carmen, Garrido, Olivier, Micheau, 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 ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), ANR-11-LABX-0021-01-LipSTIC Labex, Conseil Regional de Bourgogne, Institut National du Cancer PLBIO14-007, Ministère de la recherche, Ligue Nationale contre le Cancer, ANR-07-PCVI-0031,PCVI,A multivalent peptide library approach to identify functional TRAIL mimetics ( 2007 ), ANR-10-BLAN-1241,SphingoDR,Sensibilisation de cellules cancéreuses résistantes aux ligands des récepteurs de mort par modulation des sphingolipides de la membrane plasmique. ( 2010 ), 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, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, ANR-07-PCVI-0031,ApoMULTI-LIB,A multivalent peptide library approach to identify functional TRAIL mimetics(2007), ANR-10-BLAN-1241,SphingoDR,Sensibilisation de cellules cancéreuses résistantes aux ligands des récepteurs de mort par modulation des sphingolipides de la membrane plasmique.(2010), 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, BLANC - Sensibilisation de cellules cancéreuses résistantes aux ligands des récepteurs de mort par modulation des sphingolipides de la membrane plasmique. - - SphingoDR2010 - ANR-10-BLAN-1241 - BLANC - VALID, and 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)

Subjects
[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract

TRAIL is involved in immune tumor surveillance and is considered a promising anti-cancer agent owing to its limited side effectson healthy cells. However, some cancer cells display resistance, or become resistant to TRAIL-induced cell death. Hyperthermiacan enhance sensitivity to TRAIL-induced cell death in various resistant cancer cell lines, including lung, breast, colon or prostatecarcinomas. Mild heat shock treatment has been proposed to restore Fas ligand or TRAIL-induced apoptosis through c-FLIPdegradation or the mitochondrial pathway. We demonstrate here that neither the mitochondria nor c-FLIP degradation are requiredfor TRAIL-induced cell death restoration during hyperthermia. Our data provide evidence that insolubilization of c-FLIP, alone, issufficient to enhance apoptosis induced by death receptors. Hyperthermia induced c-FLIP depletion from the cytosolic fraction,without apparent degradation, thereby preventing c-FLIP recruitment to the TRAIL DISC and allowing efficient caspase-8 cleavageand apoptosis. Hyperthermia-induced c-FLIP depletion was independent of c-FLIP DED2 FL chain assembly motif orubiquitination-mediated c-FLIP degradation, as assessed using c-FLIP point mutants on lysine 167 and 195 or threonine 166,a phosphorylation site known to regulate ubiquitination of c-FLIP. Rather, c-FLIP depletion was associated with aggregation,because addition of glycerol not only prevented the loss of c-FLIP from the cytosol but also enabled c-FLIP recruitment within theTRAIL DISC, thus inhibiting TRAIL-induced apoptosis during hyperthermia. Altogether our results demonstrate that c-FLIP is athermosensitive protein whose targeting by hyperthermia allows restoration of apoptosis induced by TNF ligands, includingTRAIL. Our findings suggest that combining TRAIL agonists with whole-body or localized hyperthermia may be an interestingapproach in cancer therapy.

Published
2015
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10. 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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11. 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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