Monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) induces apoptosis in primary renal cell carcinoma cells in vitro and inhibits tumor growth in vivo.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a variety of tumor cells through two of its receptors: TRAIL-R1 and TRAIL-R2. We investigate the susceptibility of human renal cell carcinoma (RCC) cells to TRM-1 and HGS-ETR2, 2 human monoclonal agonistic antibodies specific for TRAIL-R1 and TRAIL-R2, respectively. HGS-ETR2 effectively induced apoptotic cell death in 10 of 11 cell cultures, including 2 human RCC cell lines and 9 human primary RCC cell cultures, with a more pronounced effect after preincubation with anti-human IgG Fc. In contrast, TRM-1 was effective in only 1 primary RCC cell culture. The increased effectiveness of HGS-ETR2 for inducing cell death might have been affected by differences in the cell-surface expression of the 2 TRAIL receptors, namely that TRAIL-R2 but not TRAIL-R1 was frequently expressed in most of the RCC cells tested. The activities of caspase-9, -8, -6, and -3 were increased with HGS-ETR2-induced apoptosis, and cell death could be blocked by specific caspase inhibitors for caspase-9, -8, and -3, and the general caspase inhibitor. In vivo administration of HGS-ETR2 with or without cross-linker significantly suppressed tumor growth of subcutaneously inoculated human RCC xenografts in immunodeficient mice. These results suggest the potential utility of TRAIL-R2 antibody as a novel therapeutic agent in RCC.
Zeng
Y
Y
Department of Urology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Wu
X X
XX
Fiscella
M
M
Shimada
O
O
Humphreys
R
R
Albert
V
V
Kakehi
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000517:prevention & control*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C510234:lexatumumab; D020169:Caspases