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

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 proceeding › Conference contribution › Academic › peer-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 language	English
Title of host publication	ADVANCES IN TNF FAMILY RESEARCH
Editors	D Wallach, A Kovalenko, M Feldman
Publisher	SPRINGER-VERLAG BERLIN
Pages	808-808
Number of pages	1
Volume	691
ISBN (Electronic)	978-1-4419-6612-4
ISBN (Print)	978-1-4419-6611-7
Publication status	Published - 2011
Event	12th Biennial International Tumor Necrosis Factor Conference - Madrid, Spain Duration: 26-Apr-2009 → 29-Apr-2009

Publication series

Name	Advances in Experimental Medicine and Biology
Publisher	SPRINGER-VERLAG BERLIN
Volume	691
ISSN (Print)	0065-2598

Conference

Conference	12th Biennial International Tumor Necrosis Factor Conference
Country/Territory	Spain
City	Madrid
Period	26/04/2009 → 29/04/2009

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Szegezdi, E., van der Sloot, A. M., Alessandro, N., Mahalingam, D., Cool, R. H., Munoz, I. G., Montoya, G., Quax, W. J., Luis Serrano, S. D. J., & Samali, A. (2011). IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION. In D. Wallach, A. Kovalenko, & M. Feldman (Eds.), ADVANCES IN TNF FAMILY RESEARCH (Vol. 691, pp. 808-808). (Advances in Experimental Medicine and Biology; Vol. 691). SPRINGER-VERLAG BERLIN.

@inproceedings{3f1f2e2b506548f88ab6648ee043431e,

title = "IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION",

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 (singlemutant, D269H, and double mutant D296H/E195R) engineered to selectively activateDR5 but not DR4 enhanced pro-caspase-8 processing and apoptosis in tumorcells, compared to wild-type TRAIL. D269H/E195R showed a 17 fold faster kineticsof receptor activation than wild-type TRAIL. The robust receptor activation wasnot due to altered 3D ligand structures or aggregation but to high affinity and selectivitytowards DR5, which prevented ligand-induced receptor heteromerization andneutralization by decoys. These findings have important implications for the designof anticancer therapeutic agents and cytokine engineering.",

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

year = "2011",

language = "English",

isbn = "978-1-4419-6611-7",

volume = "691",

series = "Advances in Experimental Medicine and Biology",

publisher = "SPRINGER-VERLAG BERLIN",

pages = "808--808",

editor = "D Wallach and A Kovalenko and M Feldman",

booktitle = "ADVANCES IN TNF FAMILY RESEARCH",

note = "12th Biennial International Tumor Necrosis Factor Conference ; Conference date: 26-04-2009 Through 29-04-2009",

}

Szegezdi, E, van der Sloot, AM, Alessandro, N, Mahalingam, D, Cool, RH, Munoz, IG, Montoya, G, Quax, WJ, Luis Serrano, SDJ & Samali, A 2011, IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION. in D Wallach, A Kovalenko & M Feldman (eds), ADVANCES IN TNF FAMILY RESEARCH. vol. 691, Advances in Experimental Medicine and Biology, vol. 691, SPRINGER-VERLAG BERLIN, pp. 808-808, 12th Biennial International Tumor Necrosis Factor Conference, Madrid, Spain, 26/04/2009.

IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION. / Szegezdi, Eva; van der Sloot, Almer M.; Alessandro, Natoni et al.
ADVANCES IN TNF FAMILY RESEARCH. ed. / D Wallach; A Kovalenko; M Feldman. Vol. 691 SPRINGER-VERLAG BERLIN, 2011. p. 808-808 (Advances in Experimental Medicine and Biology; Vol. 691).

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution › Academic › peer-review

TY - GEN

T1 - IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION

AU - Szegezdi, Eva

AU - van der Sloot, Almer M.

AU - Alessandro, Natoni

AU - Mahalingam, Devalingam

AU - Cool, Robbert H.

AU - Munoz, Ines G.

AU - Montoya, Guillermo

AU - Quax, Wim J.

AU - Luis Serrano, Steven de Jong

AU - Samali, Afshin

PY - 2011

Y1 - 2011

N2 - 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 (singlemutant, D269H, and double mutant D296H/E195R) engineered to selectively activateDR5 but not DR4 enhanced pro-caspase-8 processing and apoptosis in tumorcells, compared to wild-type TRAIL. D269H/E195R showed a 17 fold faster kineticsof receptor activation than wild-type TRAIL. The robust receptor activation wasnot due to altered 3D ligand structures or aggregation but to high affinity and selectivitytowards DR5, which prevented ligand-induced receptor heteromerization andneutralization by decoys. These findings have important implications for the designof anticancer therapeutic agents and cytokine engineering.

AB - 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 (singlemutant, D269H, and double mutant D296H/E195R) engineered to selectively activateDR5 but not DR4 enhanced pro-caspase-8 processing and apoptosis in tumorcells, compared to wild-type TRAIL. D269H/E195R showed a 17 fold faster kineticsof receptor activation than wild-type TRAIL. The robust receptor activation wasnot due to altered 3D ligand structures or aggregation but to high affinity and selectivitytowards DR5, which prevented ligand-induced receptor heteromerization andneutralization by decoys. These findings have important implications for the designof anticancer therapeutic agents and cytokine engineering.

M3 - Conference contribution

SN - 978-1-4419-6611-7

VL - 691

T3 - Advances in Experimental Medicine and Biology

SP - 808

EP - 808

BT - ADVANCES IN TNF FAMILY RESEARCH

A2 - Wallach, D

A2 - Kovalenko, A

A2 - Feldman, M

PB - SPRINGER-VERLAG BERLIN

T2 - 12th Biennial International Tumor Necrosis Factor Conference

Y2 - 26 April 2009 through 29 April 2009

ER -

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

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