Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Int J Oncol. 2011 Feb;38(2):365-74. doi: 10.3892/ijo.2010.874. Epub 2010 Dec 15.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising anti-cancer agents, but some tumor types develop resistance to TRAIL. Here, we report that chetomin, an inhibitor of hypoxia-inducible factors, is a potent enhancer of TRAIL-induced apoptosis. TRAIL or chetomin alone weakly induced apoptosis, but the combination of chetomin and TRAIL synergistically induced apoptosis in prostate cancer PC-3 cells. The combination of chetomin and TRAIL induces the activation of caspase-3, -8, -9 and -10. Among the apoptotic factors related to the TRAIL pathway, chetomin markedly decreased the X-linked inhibitor of apoptosis (XIAP) protein levels in a dose-dependent manner, but other IAP family members, TRAIL receptors and Bcl-2 family members were not altered by chetomin. Using XIAP siRNA instead of chetomin, down-regulation of XIAP sensitized PC-3 cells to TRAIL-induced apoptosis. Conversely, transient transfection of XIAP reduced the apoptotic response to combined treatment with chetomin and TRAIL. Treatment with chetomin induced a rapid decrease in XIAP protein levels but had no effect on XIAP mRNA levels. Since chetomin-mediated XIAP down-regulation was completely prevented by proteasome inhibitors, it was suggested that chetomin induces the degradation of the XIAP protein in a proteasome-dependent manner. Additionally, chetomin also sensitized renal cancer Caki-1 cells and bladder cancer UM-UC-3 cells to TRAIL-induced apoptosis via down-regulation of XIAP. Co-treatment of chetomin and TRAIL did not enhance apoptosis in normal peripheral blood mononuclear cells (PBMC). Taken together, these findings suggest that TRAIL and chetomin synergistically induce apoptosis in human urogenital cancer cells through a mechanism that involves XIAP down-regulation by chetomin.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是最有前途的抗癌药物之一，但有些肿瘤类型对 TRAIL 产生耐药性。在这里，我们报告说，低氧诱导因子抑制剂 chetomin 是 TRAIL 诱导凋亡的有效增强剂。TRAIL 或 chetomin 单独诱导凋亡作用较弱，但 chetomin 和 TRAIL 的联合使用可协同诱导前列腺癌 PC-3 细胞凋亡。chetomin 和 TRAIL 的联合使用诱导 caspase-3、-8、-9 和 -10 的激活。在与 TRAIL 途径相关的凋亡因子中，chetomin 呈剂量依赖性地显著降低 X 连锁凋亡抑制剂（XIAP）蛋白水平，但其他 IAP 家族成员、TRAIL 受体和 Bcl-2 家族成员不受 chetomin 影响。使用 XIAP siRNA 代替 chetomin，下调 XIAP 可使 PC-3 细胞对 TRAIL 诱导的凋亡敏感。相反，XIAP 的瞬时转染降低了对 chetomin 和 TRAIL 联合治疗的凋亡反应。chetomin 处理可迅速降低 XIAP 蛋白水平，但对 XIAP mRNA 水平没有影响。由于 chetomin 介导的 XIAP 下调完全被蛋白酶体抑制剂所阻止，因此表明 chetomin 以依赖于蛋白酶体的方式诱导 XIAP 蛋白降解。此外，chetomin 还通过下调 XIAP 使肾癌细胞 Caki-1 和膀胱癌 UM-UC-3 细胞对 TRAIL 诱导的凋亡敏感。chetomin 和 TRAIL 的联合治疗并未增强正常外周血单核细胞（PBMC）的凋亡。综上所述，这些发现表明，TRAIL 和 chetomin 通过 chetomin 下调 XIAP 的机制协同诱导人泌尿生殖系统癌细胞凋亡。
