A small molecule induces integrin β4 nuclear translocation and apoptosis selectively in cancer cells with high expression of integrin β4.
A small molecule induces integrin β4 nuclear translocation and apoptosis selectively in cancer cells with high expression of integrin β4.
复制标题
DOI：
10.18632/oncotarget.7646
复制
发表时间：
2016-03-29
期刊：
影响因子：
--
通讯作者：
Zhao BX
中科院分区：
文献类型：
--
作者：
Liu SY;Ge D;Chen LN;Zhao J;Su L;Zhang SL;Miao JY;Zhao BX
整合素β4 （ITGB4）水平升高伴随着多发性癌的恶性进展。然而，针对高水平表达ITGB4的癌细胞的选择性治疗策略尚未报道。在这里，我们首次报道了一种手性小分子SEC通过诱导ITGB4核易位，选择性地促进高水平表达ITGB4的癌细胞的凋亡。核ITGB4可以结合ATF3启动子区，激活ATF3的表达，进而上调下游促凋亡基因。此外，SEC促进了annexin A7 （ANXA7）与ITGB4的结合，提高了ANXA7 GTPase的活性。激活的ANXA7通过触发ITGB4在Y1494位点的磷酸化促进ITGB4核易位。SEC还能抑制异种移植瘤在禽类胚胎模型中的生长。我们发现了一个小分子SEC，通过触发ITGB4和ANXA7的结合、ITGB4核运输和促凋亡基因的表达，在体外和体内对ITGB4高表达的癌细胞具有选择性促凋亡作用。
Increased integrin β4 (ITGB4) level is accompanied by malignant progression of multiple carcinomas. However, selective therapeutic strategies against cancer cells expressing a high level of ITGB4 have not been reported. Here, for the first time, we report that a chiral small molecule, SEC, selectively promotes apoptosis in cancer cells expressing a high level of ITGB4 by inducing ITGB4 nuclear translocation. Nuclear ITGB4 can bind to the ATF3 promoter region and activate the expression of ATF3, then upregulate the downstream pro-apoptosis genes. Furthermore, SEC promoted the binding of annexin A7 (ANXA7) to ITGB4 and increased ANXA7 GTPase activity. Activated ANXA7 promoted ITGB4 nuclear translocation by triggering ITGB4 phosphorylation at Y1494. SEC also inhibited the growth of xenograft tumors in the avian embryo model. We identified a small molecule, SEC, with selective pro-apoptosis effects on cancer cells with high expression of ITGB4, both in vitro and in vivo, by triggering the binding of ITGB4 and ANXA7, ITGB4 nuclear trafficking, and pro-apoptosis gene expression.