Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the dr5 receptor
van der Sloot, A. M.
Mullally, M. M.
Cool, R. H.
Quax, W. J.
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van der Sloot, A. M. Tur, V.; Szegezdi, E.; Mullally, M. M.; Cool, R. H.; Samali, A.; Serrano, L.; Quax, W. J. (2006). Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the dr5 receptor. Proceedings of the National Academy of Sciences 103 (23), 8634-8639
Tumor necrosis factor-related apoptosis-inclucing ligand (TRAIL) is a potential anticancer drug that selectively induces apoptosis in a variety of cancer cells by interacting with death receptors DR4 and DR5. TRAIL can also bind to decoy receptors (DcR1, DcR2, and osteoprotegerin receptor) that cannot induce apoptosis. The occurrence of DR5-responsive tumor cells indicates that a DR5 receptor-specific TRAIL variant will permit tumor-selective therapies. By using the automatic design algorithm FOLD-X, we successfully generated DR5-selective TRAIL variants. These variants do not induce apoptosis in DR4-responsive cell lines but show a large increase in biological activity in DR5-responsive cancer cell lines. Even wild-type TRAIL-insensitive ovarian cancer cell lines could be brought into apoptosis. In addition, our results demonstrate that there is no requirement for anti body-mediated cross-linking or membrane-bound TRAIL to induce apoptosis through DRS.