ARAN - Access to Research at NUI Galway

Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variants

ARAN - Access to Research at NUI Galway

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dc.contributor.author Natoni, Alessandro en
dc.contributor.author Szegezdi, Eva en
dc.contributor.author Samali, Afshin en
dc.date.accessioned 2011-05-23T10:26:32Z en
dc.date.available 2011-05-23T10:26:32Z en
dc.date.issued 2010 en
dc.identifier.citation C R Reis,C,R.,van der Sloot,A. M., Natoni,A.,Szegezdi,E., Setroikromo,R.,Meijer,M.,Sjollema, K.,Stricher, F.,Cool,R.H.,Samali, A., Serrano,L. & Quax, W. J. (2010) Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variants. Cell Death and Disease 1, e83; doi:10.1038/cddis.2010.61 en
dc.identifier.uri http://hdl.handle.net/10379/1930 en
dc.description.abstract 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. en
dc.format application/pdf en
dc.language.iso en en
dc.publisher Macmillan Publishers Limited en
dc.subject Apoptosis en
dc.subject TRAIL en
dc.subject Death receptors en
dc.subject Homotrimerization en
dc.subject Biochemistry en
dc.title Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variants en
dc.type Article en
dc.local.publishedsource http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035906/ en
dc.description.peer-reviewed peer-reviewed en

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