Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor

doi:10.1073/pnas.0510187103

Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor

*Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands;
^‡Structural Biology and Biocomputing Program, European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany; and
^§Cell Stress and Apoptosis Research Group, Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland

Edited by Stephen L. Mayo, California Institute of Technology, Pasadena, CA, and approved April 12, 2006
↵ ^†A.M.v.d.S. and V.T. contributed equally to this paper. (received for review December 1, 2005)

Abstract

Tumor necrosis factor-related apoptosis-inducing 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 antibody-mediated cross-linking or membrane-bound TRAIL to induce apoptosis through DR5.

Footnotes

^‖To whom correspondence should be addressed. E-mail: w.j.quax{at}rug.nl
↵ ^¶Present address: Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6525 GA, Nijmegen, The Netherlands.
Author contributions: A.M.v.d.S., V.T., E.S., M.M.M., R.H.C., A.S., L.S., and W.J.Q. designed research; A.M.v.d.S., V.T., and E.S. performed research; A.M.v.d.S., V.T., E.S., M.M.M., R.H.C., A.S., L.S., and W.J.Q. wrote the paper; and M.M.M. initiated the project.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

OPG,

osteoprotegerin;

SPR,

surface plasmon resonance;

TNF,

tumor necrosis factor;

TRAIL,

TNF-related apoptosis-inducing ligand.