Human agonistic antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2 induces cytotoxicity and apoptosis in prostate cancer and bladder cancer cells.
OBJECTIVE
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumor cells through two of its receptors: TRAIL-R1 and TRAIL-R2. In this study, we investigated the susceptibility of human prostate cancer and bladder cancer cells to HGS-ETR2, a human monoclonal agonistic antibody specific for TRAIL-R2.


METHODS
The cell surface expression of TRAIL-R1 and TRAIL-R2 on prostate cancer and bladder cancer cells was determined using flow cytometry. Cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and caspase activities were measured by a quantitative colorimetric assay.


RESULTS
HGS-ETR2 effectively induced apoptotic cell death in DU145, PC3, and LNCaP human prostate cancer cells and J82 and T24 human bladder cancer cells. The increased effectiveness of HGS-ETR2 for inducing cell death might have been affected by differences in the cell surface expression of the two TRAIL receptors, in that TRAIL-R2, but not TRAIL-R1, was frequently expressed in the prostate cancer and bladder cancer cells. HGS-ETR2 significantly activated the caspase cascade, including caspase-3, -6, -8, and -9, which were the downstream molecules of the death receptors in prostate cancer cells. Caspase-3, -6, and -9 were also significantly activated with HGS-ETR2-induced apoptosis in the bladder cancer cells.


CONCLUSIONS
These findings suggest the potential utility of TRAIL-R2 antibody as a novel therapeutic agent against prostate cancer and bladder cancer.
Shimada
Osamu
O
Department of Urology, Kagawa University Faculty of Medicine, Kagawa, Japan.
Wu
Xiuxian
X
Jin
Xinghua
X
Nouh
Mohammed Ahmed Abdel-Muneem
MA
Fiscella
Michele
M
Albert
Vivian
V
Matsuda
Tadashi
T
Kakehi
Yoshiyuki
Y
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D011336:Probability; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology
D051017:Apoptosis Regulatory Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047889:Receptors, Tumor Necrosis Factor, Type II; D020169:Caspases