Oncotarget

Research Papers:

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

Neila Chekkat, Caterina M. Lombardo, Cendrine Seguin, Marie-Charlotte Lechner, Florent Dufour, Yves Nominé, Marcella De Giorgi, Benoit Frisch, Olivier Micheau, Gilles Guichard, Danièle Altschuh and Sylvie Fournel _

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Oncotarget. 2018; 9:15566-15578. https://doi.org/10.18632/oncotarget.24526

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Abstract

Neila Chekkat1, Caterina M. Lombardo2,3, Cendrine Seguin1, Marie-Charlotte Lechner2,3, Florent Dufour4, Yves Nominé6,7, Marcella De Giorgi1, Benoit Frisch1,5, Olivier Micheau4, Gilles Guichard2,3, Danièle Altschuh6,7,* and Sylvie Fournel1,*

1Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS, Université de Strasbourg, 67401 Illkirch, France

2Université de Bordeaux, CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 33607 Pessac, France

3CNRS, CBMN, UMR 5248, 33600 Pessac, France

4Centre de Recherche Lipide, Nutrition et Cancer, UMR1231 Inserm, Université de Bourgogne Franche-Comté, UFR des Sciences de Santé, F21000 Dijon, France

5International Center of Frontier Research in Chemistry, F67083 Strasbourg, France

6Equipe labellisée Ligue 2015, UMR 7242, Université de Strasbourg, CNRS, ESBS, 67412 Illkirch, France

7Present address : Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France

*Co-last authors

Correspondence to:

Sylvie Fournel, email: s.fournel@unistra.fr

Danièle Altschuh, email: altschud@igbmc.fr

Keywords: TRAIL-R2; signaling; interactions; binding modes; agonist peptides

Received: January 13, 2016     Accepted: February 12, 2018     Epub: February 17, 2018     Published: March 20, 2018

ABSTRACT

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.


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