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Reis, CR,van der Sloot, AM,Natoni, A,Szegezdi, E,Setroikromo, R,Meijer, M,Sjollema, K,Stricher, F,Cool, RH,Samali, A,Serrano, L,Quax, WJ
2010
October
Cell Death & Disease
Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variants
Published
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apoptosis TRAIL death receptors homotrimerization FADD-DEPENDENT APOPTOSIS NF-KAPPA-B LIGAND TRAIL SELECTIVE MUTANTS DECOY RECEPTORS DR5 APO2L/TRAIL CASPASE-8 DOMAIN INHIBITION
1
The tumour necrosis factor family member TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in a variety of cancer cells through the activation of death receptors 4 (DR4) and 5 (DR5) and is considered a promising anticancer therapeutic agent. As apoptosis seems to occur primarily via only one of the two death receptors in many cancer cells, the introduction of DR selectivity is thought to create more potent TRAIL agonists with superior therapeutic properties. By use of a computer-aided structure-based design followed by rational combination of mutations, we obtained variants that signal exclusively via DR4. Besides an enhanced selectivity, these TRAIL-DR4 agonists show superior affinity to DR4, and a high apoptosis-inducing activity against several TRAIL-sensitive and -resistant cancer cell lines in vitro. Intriguingly, combined treatment of the DR4-selective variant and a DR5-selective TRAIL variant in cancer cell lines signalling by both death receptors leads to a significant increase in activity when compared with wild-type rhTRAIL or each single rhTRAIL variant. Our results suggest that TRAIL induced apoptosis via high-affinity and rapid-selective homotrimerization of each DR represent an important step towards an efficient cancer treatment. Cell Death and Disease (2010) 1, e83; doi: 10.1038/cddis.2010.61; published online 21 October 2010
ARTN e83
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