Post-translational modification of TRAIL receptor type 1 on various tumor cells and the susceptibility of tumors to TRAIL-induced apoptosis.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R1 and TRAIL-R2) are promising targets for tumor therapy. However, their clinical use is limited because some tumors show resistance to TRAIL-treatment. Here, we analyzed epitopes of nine TRAIL-R1-specific human monoclonal antibodies and demonstrated at least five tentative epitopes on human TRAIL-R1. We found that some of the five were post-translationally modified on some tumor cell lines. Interestingly, one of them, an epitope of TR1-272 antibody (TR1-272-epitope) disappeared on the tumor cells that are more susceptible to TRAIL-induced apoptosis compared to TR1-272-epitope positive cells. Treatment of TR1-272-epitope negative cells with TRAIL induced large cluster formation of TRAIL-R1, while treatment of TR1-272-epiope positive cells with TRAIL did not. These results suggest that TR1-272-antibody might distinguish the TRAIL-R1 conformation that could deliver stronger death signals. Further analysis of epitope-appearance and sensitivity to TRAIL should clarify the mechanisms of TRAIL-induced apoptosis of tumor cells and would provide useful information about tumor therapy using TRAIL and TRAIL-R signaling.
Lin
Zhezhu
Z
Department of Immunology, University of Toyama, Sugitani, Toyama 930-0194, Japan.
Jin
Aishun
A
Ozawa
Tatsuhiko
T
Tajiri
Kazuto
K
Obata
Tsutomu
T
Ishida
Isao
I
Jin
Feng
F
Kishi
Hiroyuki
H
Muraguchi
Atsushi
A
D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000939:Epitopes; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human