Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells
Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells
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DOI：
10.1093/carcin/bgl015
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发表时间：
2006-09-01
期刊：
影响因子：
4.7
通讯作者：
Sakai, Toshiyuki
中科院分区：
文献类型：
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作者：
Matsui, Taka-Aki;Sowa, Yoshihiro;Sakai, Toshiyuki
萝卜硫素（SFN）是一种天然存在的异硫氰酸酯，由于其有效的抗癌作用而成为一种有吸引力的药物。SFN在体外和体内抑制各种癌细胞的增殖。肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）也是最有希望的肿瘤治疗药物之一。在这项研究中，我们报告SFN增强TRAIL诱导的人骨肉瘤细胞Saos 2和MG 63的凋亡。由SFN和TRAIL共同处理诱导的细胞凋亡被显性负性形式的TRAIL受体或半胱天冬酶抑制剂显著阻断。SFN和TRAIL的组合使用有效地诱导Bid切割和半胱天冬酶8、10、9和3的活化，对于每种试剂在无效浓度下。SFN在mRNA和蛋白水平上以剂量依赖性方式上调死亡受体5（DR 5）的表达，DR 5是TRAIL的受体。此外，SFN介导的对TRAIL的致敏作用被DR 5 siRNA降低，表明致敏作用至少部分是通过诱导DR 5表达介导的。此外，SFN敏化TRAIL诱导的凋亡在p53非依赖性的方式。另一方面，SFN既不诱导DR 5蛋白表达，也不增强TRAIL诱导的正常人外周血单个核细胞凋亡。因此，SFN和TRAIL联合治疗骨肉瘤可能是一种有前途的治疗方法。
Sulforaphane (SFN), a naturally occurring isothiocyanate, is an attractive agent because of its potent anticancer effects. SFN suppresses the proliferation of various cancer cells in vitro and in vivo. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is also one of the most promising candidates for cancer therapeutics owing to its ability to selectively induce apoptosis in tumor cells. In this study, we report that SFN enhances TRAIL-induced apoptosis in human osteosarcoma cells, Saos2 and MG63. The apoptosis induced by co-treatment with SFN and TRAIL was markedly blocked by a dominant negative form of the TRAIL receptor or caspase inhibitors. The combined use of SFN and TRAIL effectively induced Bid cleavage and the activation of caspases 8, 10, 9 and 3 at ineffective concentrations for each agent. SFN upregulated the expression of death receptor 5 (DR5), a receptor for TRAIL, at mRNA and protein levels in a dose-dependent manner. In addition, the SFN-mediated sensitization to TRAIL was reduced by DR5 siRNA, suggesting that the sensitization was at least partially mediated through the induction of DR5 expression. Furthermore, SFN sensitized TRAIL-induced apoptosis in a p53-independent manner. On the other hand, SFN neither induced DR5 protein expression or enhanced TRAIL-induced apoptosis in normal human peripheral blood mononuclear cells. Thus, combined treatment with SFN and TRAIL might be a promising therapy for osteosarcoma.