Shimada Osamu, Wu Xiuxian, Jin Xinghua, Nouh Mohammed Ahmed Abdel-Muneem, Fiscella Michele, Albert Vivian, Matsuda Tadashi, Kakehi Yoshiyuki
Department of Urology, Kagawa University Faculty of Medicine, Kagawa, Japan.
Urology. 2007 Feb;69(2):395-401. doi: 10.1016/j.urology.2006.12.007.
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.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）通过其两种受体TRAIL-R1和TRAIL-R2诱导多种肿瘤细胞凋亡。在本研究中，我们调查了人前列腺癌细胞和膀胱癌细胞对HGS-ETR2（一种针对TRAIL-R2的人源单克隆激动抗体）的敏感性。
使用流式细胞术测定前列腺癌细胞和膀胱癌细胞上TRAIL-R1和TRAIL-R2的细胞表面表达。通过3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐法评估细胞毒性，并通过定量比色法测量半胱天冬酶活性。
HGS-ETR2有效诱导DU145、PC3和LNCaP人前列腺癌细胞以及J82和T24人膀胱癌细胞发生凋亡性细胞死亡。HGS-ETR2诱导细胞死亡有效性的增加可能受到两种TRAIL受体细胞表面表达差异的影响，因为TRAIL-R2而非TRAIL-R1在前列腺癌细胞和膀胱癌细胞中经常表达。HGS-ETR2显著激活了半胱天冬酶级联反应，包括半胱天冬酶-3、-6、-8和-9，它们是前列腺癌细胞中死亡受体的下游分子。在膀胱癌细胞中，HGS-ETR2诱导的凋亡也显著激活了半胱天冬酶-3、-6和-9。
这些发现表明TRAIL-R2抗体作为一种针对前列腺癌和膀胱癌的新型治疗药物具有潜在应用价值。
