IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION

Eva Szegezdi, Almer M. van der Sloot, Natoni Alessandro, Devalingam Mahalingam, Robbert H. Cool, Ines G. Munoz, Guillermo Montoya, Wim J. Quax, Steven de Jong Luis Serrano, Afshin Samali

Research output: Chapter in Book/Report/Conference proceedingConference contributionAcademicpeer-review

Abstract

Apoptosis can be activated by tumor necrosis factor-related apoptosis-inducing ligand
(TRAIL) in a wide range of tumor cells, but not in non-transformed cells.
TRAIL interaction with receptors DR4 or DR5 induces apoptosis, whereas DcR1,
DcR2 and osteoprotegerin are decoy receptors for TRAIL. TRAIL variants (single
mutant, D269H, and double mutant D296H/E195R) engineered to selectively activate
DR5 but not DR4 enhanced pro-caspase-8 processing and apoptosis in tumor
cells, compared to wild-type TRAIL. D269H/E195R showed a 17 fold faster kinetics
of receptor activation than wild-type TRAIL. The robust receptor activation was
not due to altered 3D ligand structures or aggregation but to high affinity and selectivity
towards DR5, which prevented ligand-induced receptor heteromerization and
neutralization by decoys. These findings have important implications for the design
of anticancer therapeutic agents and cytokine engineering.
Original languageEnglish
Title of host publicationADVANCES IN TNF FAMILY RESEARCH
EditorsD Wallach, A Kovalenko, M Feldman
PublisherSPRINGER-VERLAG BERLIN
Pages808-808
Number of pages1
Volume691
ISBN (Electronic)978-1-4419-6612-4
ISBN (Print)978-1-4419-6611-7
Publication statusPublished - 2011
Event12th Biennial International Tumor Necrosis Factor Conference - Madrid, Spain
Duration: 26-Apr-200929-Apr-2009

Publication series

NameAdvances in Experimental Medicine and Biology
PublisherSPRINGER-VERLAG BERLIN
Volume691
ISSN (Print)0065-2598

Conference

Conference12th Biennial International Tumor Necrosis Factor Conference
CountrySpain
CityMadrid
Period26/04/200929/04/2009

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