Abstract
The proapoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors death receptor (DR) 4 and DR5 are attractive targets to develop the receptor-specific agonistic monoclonal antibodies (mAb) as anticancer agents because of their tumor-selective cell death-inducing activity. Here, we report a novel agonistic mAb, AY4, raised against human DR4 in mice. ELISA analysis revealed that AY4 specifically bound to DR4 without competition with TRAIL for the binding. Despite distinct binding regions of AY4 on DR4 from those of TRAIL, AY4 as a single agent induced caspase-dependent apoptotic cell death of several tumor types through the extrinsic and/or intrinsic pathways without substantial cytotoxicity to normal human hepatocytes. Further, the AY4-sensitive cells followed the same cell death characteristics classified as type I and type II cells by the response to TRAIL, suggesting that the cell death profiles in responses to DR4 and/or DR5 stimulation are determined by the downstream signaling of the receptor rather than the kind of receptor. Noticeably, AY4 efficiently induced cell death of Jurkat cells, which have been reported to be resistant to other anti-DR4 agonistic mAbs, most likely due to the unique epitope property of AY4. In vivo administration of AY4 significantly inhibited tumor growth of human non-small cell lung carcinoma preestablished in athymic nude mice. Conclusively, our results provide further insight into the DR4-mediated cell death signaling and potential use of AY4 mAb as an anticancer therapeutic agent, particularly for DR4-responsive tumor types.
Highlights
The proapoptotic tumor necrosis factor–related apoptosis inducing ligand (TRAIL) receptors death receptor (DR) 4 (TRAIL-R1) and DR5 (TRAIL-R2) are attractive targets for development of agonistic anticancer agents because they are widely expressed in many tumors and can selectively kill tumor cells with little cytotoxicity on normal cells in vitro and in vivo [1,2,3]
These results showed that AY4 recognizes epitopes that are specific for DR4 but not shared by the other homologous TRAIL receptors
The cell death induced by anti-DR4 monoclonal antibodies (mAb) AY4 was characterized by caspase-dependent apoptosis, which could be blocked by Z-VAD-fmk (Figs. 3 and 4)
Summary
The proapoptotic tumor necrosis factor–related apoptosis inducing ligand (TRAIL) receptors death receptor (DR) 4 (TRAIL-R1) and DR5 (TRAIL-R2) are attractive targets for development of agonistic anticancer agents because they are widely expressed in many tumors and can selectively kill tumor cells with little cytotoxicity on normal cells in vitro and in vivo [1,2,3]. Binding of trimeric or multimeric TRAIL to the proapoptotic receptors results in the receptor clustering to activate the intracellular death domain, promoting the formation of death-inducing signaling complex (DISC) by recruiting Fas-associated death domain (FADD) and caspase-8, which can subsequently trigger apoptosis signaling through the extrinsic and/or intrinsic pathways In some cells (designated type I cells), caspase-8 activation is sufficient to activate the effector caspases to execute apoptosis via the extrinsic pathway, whereas, in other cells (designated type II cells), amplification of the extrinsic pathway through the intrinsic (mitochondrial) pathway is needed to commit the cells to apoptotic cell death [1, 2, 6]
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