Enhancement of TRAIL cytotoxicity by AG-490 in human ALL cells is characterized by downregulation of cIAP-1 and cIAP-2 through inhibition of Jak2/Stat3
Enhancement of TRAIL cytotoxicity by AG-490 in human ALL cells is characterized by downregulation of cIAP-1 and cIAP-2 through inhibition of Jak2/Stat3
复制标题
DOI：
10.1038/cr.2009.80
复制
发表时间：
2009-09-01
期刊：
影响因子：
44.1
通讯作者：
Marchisio, Marco
中科院分区：
文献类型：
--
作者：
Lanuti, Paola;Bertagnolo, Valeria;Marchisio, Marco
死亡诱导肿瘤坏死因子相关的凋亡诱导配体(TRAIL)选择性杀伤多种肿瘤细胞的能力已被广泛描述，但该治疗的主要问题之一是出现耐药性和可能的毒副作用。在这里，我们报告了TRAIL诱导Jurkat和SUPT1 T细胞系和人类T-ALL细胞的凋亡，但不能诱导健康受试者外周血单核细胞的凋亡。同时，TRAIL和Tyrphostin(AG-490)，一种选择性的Janus激酶2抑制剂，产生了明显的细胞毒性增强，其特征是与对照组或TRAIL单独处理的样品相比，STAT3的磷酸化显著抑制，并伴随着CIAP-1和CIAP-2mRNA水平的显著下降。特定的小干扰RNA下调CIAP-1和CIAP-2可显著增强TRAIL降低的细胞毒作用。综上所述，这些发现有力地表明，CIAP-1和CIAP-2的下调是介导TRAIL和AG-490联合治疗T细胞白血病的信号通路中的一个基本步骤。这些发现可能有助于为开发毒性较低的药理策略来治疗受TRAIL敏感白血病影响的患者开辟新的途径。
The ability of death-inducing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to selectively kill a variety of cancer cells has been largely described, but one of the major concerns with the treatment is the occurrence of drug resistance and possible toxic side effects. Here, we report that TRAIL induces apoptosis in Jurkat and SUPT1 T cell lines and in human T-ALL blasts but not in healthy subject-derived peripheral blood mononuclear cells. In parallel, the treatment with TRAIL and Tyrphostin (AG-490), a selective Janus kinase 2 inhibitor, produces an evident enhancement of cytotoxicity, characterized by a significant inhibition of Stat3 phosphorylation compared to controls or to TRAIL alone-treated samples, and associated with a dramatic decrease of both cIAP-1 and cIAP-2 mRNA levels. Downregulation of cIAP-1 and cIAP-2 by specific small interference RNAs significantly amplifies TRAIL-reduced cytotoxicity. All together, these findings strongly indicate that cIAP-1 and cIAP-2 downregulation is a fundamental step in the signaling pathways mediating the combinatorial effect of TRAIL and AG-490 on T cell leukemia. These findings may help to open new routes for the development of less toxic pharmacological strategies in the treatment of patients affected by TRAIL-sensitive leukemias.