Mechanisms of enhancement of TRAIL tumoricidal activity against human cancer cells of different origin by dipyridamole
Mechanisms of enhancement of TRAIL tumoricidal activity against human cancer cells of different origin by dipyridamole
复制标题
DOI：
10.1038/sj.onc.1211008
复制
发表时间：
2008-05-01
期刊：
影响因子：
8
通讯作者：
Sakai, T.
中科院分区：
文献类型：
--
作者：
Goda, A. E.;Yoshida, T.;Sakai, T.
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）是一种选择性靶向肿瘤细胞的细胞因子，但其疗效受到多种耐药机制的挑战。因此，本研究探讨了双嘧达莫增强TRAIL疗效的潜力及其可能的潜在机制。潘生丁显著地使p53突变的人癌细胞系：SW 480、MG 63和DU 145对TRAIL的抗肿瘤活性敏感，如通过使TRAIL能够有效地切割起始剂和执行剂半胱天冬酶所证明的。虽然潘生丁上调DR 4和DR 5，并增加其细胞表面的表达，RNA干扰显示优先依赖于DR 5。此外，潘生丁抑制生存素的表达，其重要的后果被证实的小干扰RNA。机制上，潘生丁诱导生存素表达的转录关闭伴随G（1）阻滞，其特征在于D型细胞周期蛋白和cdk 6的下调。此外，由CCAAT/增强子结合蛋白（C/EBP）同源蛋白（CHOP）诱导提供动力的转录机制负责双嘧达莫上调DR 5。重要的是，双嘧达莫诱导的TRAIL功效的增强和蛋白表达的改变独立于蛋白激酶A或蛋白激酶G。总之，本研究的结果描述了双嘧达莫作用的新机制，并强调了其作为TRAIL功效的潜在增强剂的有前途的用途。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as an attractive cytokine that selectively targets cancer cells, however its efficacy has been challenged by a number of resistance mechanisms. Therefore, the current study investigated the potential of dipyridamole to enhance TRAIL efficacy and the probable underlying mechanisms. Dipyridamole dramatically sensitized p53-mutant human cancer cell lines: SW480, MG63 and DU145, to the antitumor activity of TRAIL, as evidenced by enabling TRAIL to efficiently cleave initiator and executioner caspases. Although dipyridamole upregulated both DR4 and DR5 and increased their cell surface expression, RNA interference revealed a preferential dependence on DR5. Moreover, dipyridamole inhibited survivin expression and its important consequences were confirmed by small interfering RNA. Mechanistically, dipyridamole induced transcriptional shutdown of survivin expression accompanying G(1) arrest that was characterized by downregulation of D-type cyclins and cdk6. In addition, a transcriptional mechanism powered by CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) induction was responsible for DR5 upregulation by dipyridamole. Importantly, dipyridamole-induced enhancement of TRAIL efficacy and alterations of protein expression were independent of either protein kinase A or protein kinase G. In conclusion, findings of the present study described novel mechanisms of dipyridamole action and highlighted its promising use as a potential enhancer of TRAIL efficacy.