Human Agonistic Antibody to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 2 Induces Cytotoxicity and Apoptosis in Prostate Cancer and Bladder Cancer Cells

Department of Urology, Kagawa University Faculty of Medicine, Kagawa, Japan.
Urology (Impact Factor: 2.19). 03/2007; 69(2):395-401. DOI: 10.1016/j.urology.2006.12.007
Source: PubMed


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.
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.
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.
These findings suggest the potential utility of TRAIL-R2 antibody as a novel therapeutic agent against prostate cancer and bladder cancer.

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    • "Currently, recombinant human TRAIL is being tested in phase I clinical trials [7]. Interestingly, TRAIL has been identified as the effector molecule in intravesical BCG immunotherapy [8] and TRAIL-based therapeutics have exhibited high therapeutic potential against bladder cancer cells in vitro [9,10], suggesting that TRAIL could be a suitable intravesical agent for the treatment of bladder cancer. However, recent studies have demonstrated that many types of cancer cells, including certain bladder cancer cell lines, are intrinsically insensitive to TRAIL [11]. "
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    • "Cancer cells were then washed and samples were immediately used for flow cytometric analysis (BD FACScan, Becton Dickinson Immnunocytometry Systems, San Jose, CA, USA). The control consisted of cells in a separate tube treated with PE-labeled mouse IgG 1 or mouse IgG 2B (R&D Systems, Minneapolis, MN, USA) [26]. "
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