Relationship between the agonist activity of synthetic ligands of TRAIL-R2 and their cell surface binding modes

Autor: Chekkat, Neila, Lombardo, Caterina, Seguin, Cendrine, Lechner, Marie-Charlotte, Dufour, Florent, Nominé, Yves, De Giorgi, Marcella, Frisch, Benoît, Micheau, Olivier, Guichard, Gilles, Altschuh, Danièle, Fournel, Sylvie
Přispěvatelé: Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Immunologie et chimie thérapeutiques ( ICT ), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique ( CNRS ), 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 ), Université Bourgogne Franche-Comté ( UBFC ), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Centre d'Etudes et de Recherche sur le Médicament de Normandie ( CERMN ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Laboratoire de Conception et Application de Molécules Bioactives ( UMR 7199 CNRS/Université de Strasbourg ), 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), ANR-08-PCVI-0034,SYMULI,Probing molecular dynamics of TNFR family members upon stimulation, in the membrane of live cells(2008), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Chimie et de Biologie, 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, Université Bourgogne Franche-Comté [COMUE] (UBFC), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Ecole Supérieure de Biotechnologie de Strasbourg (ESBS), Université de Strasbourg (UNISTRA), Micheau, Olivier, Programme interdiciplinaire en physique et chimie du vivant - Probing molecular dynamics of TNFR family members upon stimulation, in the membrane of live cells - - SYMULI2008 - ANR-08-PCVI-0034 - PCV - VALID, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), 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), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Oncotarget
Oncotarget, Impact journals, In press, 〈10.18632/oncotarget.24526〉
Oncotarget, Impact journals, 2018, 9 (21), pp.15566-15578
Oncotarget, 2018, 9 (21), pp.15566-15578. ⟨10.18632/oncotarget.24526⟩
Oncotarget, Impact journals, 2018, 9 (21), pp.15566-15578. ⟨10.18632/oncotarget.24526⟩
ISSN: 1949-2553
DOI: 10.18632/oncotarget.24526〉
Popis: IF 5.168 (2016); International audience; Tumor Necrosis Factor Receptor Apoptosis Inducing Ligand (TRAIL) appears as an interesting candidate for targeted cancer therapy as it induces apoptosis in cancer cells without toxicity to normal cells. TRAIL elicits apoptosis through agonist death receptor TRAIL-R1 and TRAIL-R2 engagement. Nevertheless, recombinant soluble TRAIL and monoclonal antibodies against these receptors demonstrated insufficient efficacy in clinical trials. This may be explained by the cell-type dependency of the apoptotic response, itself influenced by the effect on ligand binding mode of factors such as the level of receptor oligomerization or glycosylation. To investigate the relation between binding mode and signaling, we used previously described synthetic divalent and monovalent peptides specific for TRAIL-R2. We measured their pro-apoptotic activity on three cancer cell lines sensitive to rhTRAIL induced-apoptosis and monitored their cell-surface binding kinetics. The two divalent peptides bound with strong affinity to TRAIL-R2 expressed on B lymphoma BJAB cells and induced a high degree of apoptosis. By contrast, the same peptides bound weakly to TRAIL-R2 expressed at the surface of the human colon cancer HCT116 or T lymphoma Jurkat cell lines and did not induce their apoptosis. Cross-linking experiments suggest that these differences could be afforded by variations in the TRAIL-R2 oligomerization state at cell surface before ligand addition. Moreover divalent peptides showed a different efficiency in BJAB apoptosis induction, and kinetic distribution analysis of the BJAB binding curves suggested subtle differences in binding mechanisms. Thus our data support a relation between the cell-surface binding mode of the peptides and their pro-apoptotic activity. In this case the precise characterization of ligand binding to the surface of living cells would be predictive of the therapeutic potential of TRAIL-R2 synthetic ligands prior to clinical trials.
Databáze: OpenAIRE
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