Abstract
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.
Highlights
Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL/Apo2L/TNFSF10) belongs to the TNF ligand superfamily [1] and triggers apoptosis
We have previously reported on synthetic peptides that bind to DR5 (TRAILmim/DR5) and induce tumor cell apoptosis in vitro and in vivo
The present study demonstrates that while the three cell lines are sensitive to a cross-linked form of TRAIL, Jurkat and HCT116 cells are resistant to apoptosis induced by the divalent form of TRAILmim/DR5 as well as by an anti-DR5 agonist monoclonal antibody
Summary
Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL/Apo2L/TNFSF10) belongs to the TNF ligand superfamily [1] and triggers apoptosis. Triggering of DR4 and DR5 results in formation of a death inducing signaling complex (DISC) leading to caspase activation and apoptosis [5]. Multiple mechanisms for TRAIL resistance that can affect many components of the TRAIL signaling pathways have been identified [8]. TRAIL-R agonists induced activation of non-cell death signaling pathways such as NFkB, MAPK, Scr, and phosphoinositide 3-kinase (reviewed in [9]). Resistance can be acquired following an inefficient receptor clustering at the membrane level, limiting DISC component recruitment [12]. To overpass these resistances, it is crucial to better characterize the mechanisms of apoptosis induction including early events occurring at the membrane level
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