Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue.
Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue.
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格尔德霉素及其 17-烯丙基-氨基-17-去甲氧基类似物增强腺病毒 MDA-7 介导的人肺癌细胞杀伤作用。
DOI：
10.1038/sj.cgt.7700989
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发表时间：
2007
影响因子：
6.4
通讯作者：
Swisher,SG
中科院分区：
文献类型：
--
作者：
Pataer,A;Bocangel,D;Chada,S;Roth,JA;Hunt,KK;Swisher,SG
我们之前的研究表明，腺病毒介导的黑色素瘤分化相关基因7（Ad-mda7）的过度表达导致双链RNA依赖性蛋白激酶（PKR）的快速诱导并激活其下游靶标，从而诱导人肺癌细胞凋亡。在此，我们报道 Ad-mda7 和苯醌安沙霉素格尔德霉素 (GA) 以高度协同的方式相互作用，诱导人肺癌细胞死亡。 Ad-mda7 和 GA 的共同给药不会改变 MDA-7 的表达，并且与进一步的 PKR 诱导和激活无关；相反，该组合增强的细胞毒性与 GA 灭活 AKT 相关。通过使用抗 E-钙粘蛋白单克隆抗体和流式细胞术进行表面染色，我们发现 Ad-mda7 和 GA 联合治疗增加了这些癌细胞中的 E-钙粘蛋白水平。 Ad-mda7 和 GA 共同治疗还通过增加 β-catenin/E-cadherin 关联来抑制肺癌细胞运动。此外，GA衍生物17-烯丙基氨基、17-去甲氧基格尔德霉素(17AAG)与Ad-mda7的组合导致A549和H460人肺癌细胞的细胞死亡增强。
Our previous studies demonstrated that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7 (Ad-mda7) leads to rapid induction of double-stranded RNA-dependent protein kinase (PKR) and activation of its downstream targets, resulting in apoptosis induction in human lung cancer cells. Here, we report that Ad-mda7 and the benzoquinone ansamycin geldanamycin (GA) interact in a highly synergistic manner to induce cell death in human lung cancer cells. Co-administration of Ad-mda7 and GA did not modify expression of MDA-7, and was not associated with further PKR induction and activation; instead the enhanced cytotoxicity of this combination was associated with inactivation of AKT by GA. By surface staining using anti-E-cadherin monoclonal antibody and flow cytometry, we found that treatment with the combination of Ad-mda7 and GA increased E-cadherin levels in these cancer cells. Ad-mda7 and GA cotreatment also inhibited lung cancer cell motility by increasing the β-catenin/E-cadherin association. Moreover, combination of GA derivative 17-allyl-amino, 17-demethoxygeldanamycin (17AAG), with Ad-mda7 resulted in enhancement of cell death in A549 and H460 human lung cancer cells.