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

dc.rights.licenseopenen_US
dc.relation.isnodouble1c034e30-28f7-43c3-aeee-5b0c823b63ce*
dc.relation.isnodouble1c13e70a-1fac-4a77-8d61-6e9bdb663740*
dc.relation.isnodouble6043434c-720b-49f8-99b8-e30f50b2115f*
dc.contributor.authorCHEKKAT, Neila
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
dc.contributor.authorLOMBARDO, Caterina Maria
dc.contributor.authorSEGUIN, Cendrine
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
dc.contributor.authorLECHNER, Marie-Charlotte
dc.contributor.authorDUFOUR, Florent
dc.contributor.authorNOMINE, Yves
dc.contributor.authorDE GIORGI, Marcella
dc.contributor.authorFRISCH, Benoit
dc.contributor.authorMICHEAU, Olivier
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
dc.contributor.authorGUICHARD, Gilles
IDREF: 084339268
dc.contributor.authorALTSCHUH, Daniele
dc.contributor.authorFOURNEL, Sylvie
dc.date.accessioned2020-04-15T14:40:47Z
dc.date.available2020-04-15T14:40:47Z
dc.date.issued2018
dc.identifier.issn1949-2553en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/4287
dc.description.abstractEnTumor 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.
dc.description.sponsorshipProbing molecular dynamics of TNFR family members upon stimulation, in the membrane of live cells - ANR-08-PCVI-0034en_US
dc.language.isoENen_US
dc.subject.enTRAIL-R2
dc.subject.ensignaling
dc.subject.eninteractions
dc.subject.enbinding modes
dc.subject.enagonist peptides
dc.title.enRelationship between the agonist activity of synthetic ligands of TRAIL-R2 and their cell surface binding modes
dc.typeArticle de revueen_US
dc.identifier.doi10.18632/oncotarget.24526
dc.subject.halChimie/Matériauxen_US
bordeaux.journalOncotargeten_US
bordeaux.page15566-15578en_US
bordeaux.volume9en_US
bordeaux.hal.laboratoriesInstitut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN) - UMR 5248
bordeaux.issue21en_US
bordeaux.institutionBordeaux INPen_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03158222
hal.version1
hal.date.transferred2021-03-03T15:39:12Z
hal.exporttrue
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Oncotarget&rft.date=2018&rft.volume=9&rft.issue=21&rft.spage=15566-15578&rft.epage=15566-15578&rft.eissn=1949-2553&rft.issn=1949-2553&rft.au=CHEKKAT,%20Neila&LOMBARDO,%20Caterina%20Maria&SEGUIN,%20Cendrine&LECHNER,%20Marie-Charlotte&DUFOUR,%20Florent&rft.genre=article


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