Synthetic ligands of death receptor 5 display a cell-selective agonistic effect at different oligomerization levels
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Julien Beyrath1,5, Neila Chekkat1,4, Cristian R. Smulski1,6, Caterina M. Lombardo2,3, Marie-Charlotte Lechner1,2,3, Cendrine Seguin4, Marion Decossas1,3,7, Maria Vittoria Spanedda4, Benoît Frisch4, Gilles Guichard2,3,*, Sylvie Fournel1,4,*
1Institut de Biologie Moléculaire et Cellulaire, UMR 3572, Laboratoire d’Immunopathologie et Chimie Thérapeutique, Strasbourg 67084, France
2Institut Européen de Chimie et Biologie, UMR 5248, Institut de Chimie & Biologie des Membranes & des Nano-objets (CBMN), Univ. Bordeaux, Pessac 33607, France
3UMR 5248, CBMN, CNRS, Pessac 33600, France
4Current address: Faculté de Pharmacie, UMR 7199, Laboratoire de Conception et Application de Molécules Bioactives, Illkirch BP 67401, France
5Current address: Khondrion BV, Nijmegen 6525EX, The Netherlands
6Current address: University Medical Center Freiburg, Center for Chronic Immunodeficiency, Freiburg D-79110, Germany
7UMR 5248, CBMN, Univ. Bordeaux, Pessac 33600, France
*These authors have shared senior authorship
Sylvie Fournel, email: firstname.lastname@example.org
Keywords: apoptosis, DR5, oligomerization, peptides, agonist
Received: July 15, 2015 Accepted: May 11, 2016 Published: July 09, 2016
DR4 (Death Receptor 4) and DR5 (Death Receptor 5) are two potential targets for cancer therapy due to their ability to trigger apoptosis of cancer cells, but not normal ones, when activated by their cognate ligand TRAIL (TNF related apoptosis-inducing ligand). Therapies based on soluble recombinant TRAIL or agonist antibodies directed against one of the receptors are currently under clinical trials. However, TRAIL-R positive tumor cells are frequently resistant to TRAIL induced apoptosis. The precise mechanisms of this resistance are still not entirely understood. We have previously reported on synthetic peptides that bind to DR5 (TRAILmim/DR5) and induce tumor cell apoptosis in vitro and in vivo. Here, we showed that while hexameric soluble TRAIL is able to efficiently kill the DR5 positive lymphoma Jurkat or the carcinoma HCT116, these cells are resistant to apoptosis induced by the divalent form of TRAILmim/DR5 and are poorly sensitive to apoptosis induced by an anti-DR5 agonist monoclonal antibody. This resistance can be restored by the cross-linking of anti-DR5 agonist antibody but not by the cross-linking of the divalent form of TRAILmim/DR5. Interestingly, the divalent form of TRAILmim/DR5 that induced apoptosis of DR5 positive BJAB cells, acts as an inhibitor of TRAIL-induced apoptosis on Jurkat and HCT116 cells. The rapid internalization of DR5 observed when treated with divalent form of TRAILmim/DR5 could explain the antagonist activity of the ligand on Jurkat and HCT116 cells but also highlights the independence of the mechanisms responsible for internalization and activation when triggering the DR5 apoptotic cascade.
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