title: Death Receptor-Induced Apoptosis Signalling Regulation by Ezrin Is Cell Type Dependent and Occurs in a DISC-Independent Manner in Colon Cancer Cells.
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.
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iessi
authors.affiliation: INSERM, U866, Dijon, F-21079, France; Pós-graduação em Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Paraná, 80215-901, Curitiba, Paraná, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Zischler
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Etringer
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Bergeret
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Morlé
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacquemin
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morizot
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Shirley
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France.
authors.forename: Najoua
authors.initials: N
authors.lastname: Lalaoui
authors.affiliation: Pós-graduação em Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Paraná, 80215-901, Curitiba, Paraná, Brazil.
authors.forename: Selene L
authors.initials: SL
authors.lastname: Elifio-Esposito
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Antitumor Drugs Section, Istituto Superiore di Sanita, Viale Regina Elena, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France; Centre Georges-François Leclerc, Dijon, F-21000, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.affiliation: INSERM, U1009, Villejuif, F-94805, France; Institut Gustave Roussy, Univ. Paris XI, Villejuif, F-94805, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: INSERM, U866, Dijon, F-21079, France; UFR des Sciences de Santé, Univ. Bourgogne, Dijon, F-21079, France; Centre Georges-François Leclerc, Dijon, F-21000, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase; D019014:fas Receptor / Q000378:metabolism; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D010088:Oxidoreductases; D010768:Phosphoserine; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D019014:fas Receptor; D000099149:Ezrin; C491901:FAS protein, human; C486071:WWOX protein, human