Adenovirus expressing dual c-Met-specific shRNA exhibits potent antitumor effect through autophagic cell death accompanied by senescence-like phenotypes in glioblastoma cells.
Adenovirus expressing dual c-Met-specific shRNA exhibits potent antitumor effect through autophagic cell death accompanied by senescence-like phenotypes in glioblastoma cells.
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DOI：
10.18632/oncotarget.3018
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发表时间：
2015-02-28
期刊：
影响因子：
--
通讯作者：
Yun CO
中科院分区：
文献类型：
--
作者：
Lee JS;Oh E;Yoo JY;Choi KS;Yoon MJ;Yun CO
c-Met 是肝细胞生长因子的同源受体酪氨酸激酶，在许多肿瘤中过度表达和/或突变。因此，消除 c-Met 信号传导可能作为潜在的治疗靶点。在本研究中，我们生成了表达 c-Met (shMet) 特异性的单 shRNA（dl/shMet4 和 dl/shMet5）或 c-Met 特异性的双 shRNA (dl/shMet4+5) 的广告；并检查了这些新设计的广告在靶向 c-Met 方面的治疗潜力，并描述了它们的体外和体内作用机制。表达 shMet 的广告诱导 c-Met 敲低，并在表型上导致类似自噬的特征，包括膜液泡的出现、酸性囊泡细胞器的形成以及微管相关蛋白 1 轻链 3 的裂解和招募至自噬体。表达 shMet 的广告还抑制 Akt 磷酸化并增加衰老相关基因产物的数量，包括 SM22、TGase II 和 PAI-1。这些变化导致 U343 细胞增殖抑制和 G2/M 期停滞。在体内，瘤内注射dl/shMet4+5导致肿瘤生长显着减少，同时总体存活率相应提高。这些治疗肿瘤的组织病理学分析表明 Atg5 高度上调，表明治疗诱导了自噬。总之，这些结果表明，表达 shMet 的 Ads 诱导的自噬细胞死亡提供了一种通过非凋亡细胞死亡机制靶向表达 c-Met 的肿瘤的新策略。
c-Met, a cognate receptor tyrosine kinase of hepatocyte growth factor, is overexpressed and/or mutated in number of tumors. Therefore, abrogation of c-Met signaling may serve as potential therapeutic targets. In this study, we generated Ads expressing single shRNA specific to c-Met (shMet) (dl/shMet4 and dl/shMet5) or dual shRNAs specific to c-Met (dl/shMet4+5); and examined the therapeutic potential of these newly engineered Ads in targeting c-Met, and delineated their mechanism of action in vitro and in vivo. Ads expressing shMet induced knock-down in c-Met, and phenotypically resulted in autophagy-like features including appearance of membranousvacuoles, formation of acidic vesicular organelles, and cleavage and recruitment of microtubule-associated protein1 light chain 3 to autophagosomes. Ads expressing shMet also suppressed Akt phosphorylation and increased number of senescence-related gene products including SM22, TGase II, and PAI-1. These changes resulted in inhibition of cell proliferation and G2/M arrest of U343 cells. In vivo, intratumoral injection with dl/shMet4+5 resulted in a significant reduction of tumor growth with corresponding increasing overall survival. Histopathological analysis of these treated tumors revealed that Atg5 was highly up-regulated, indicating the therapeutic induction of autophagy. In sum, these results reveal that autophagic cell death induced by shMet-expressing Ads provide a novel strategy for targeting c-Met-expressing tumors through non-apoptotic mechanism of cell death.
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DOI：
10.18632/aging.100443
发表时间：
2012-03
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
10.3
作者：
Ito, Hideaki;Aoki, Hiroshi;Kondo, Seiji
通讯作者：
Kondo, Seiji
影响因子：
3.8
作者：
Hasinoff, Brian B.
通讯作者：
Hasinoff, Brian B.
影响因子：
--
作者：
Chu, Shenghua;Yuan, Xianhou;Zhang, Jie
通讯作者：
Zhang, Jie
影响因子：
13.3
作者：
Aoki, Hiroshi;Kondo, Yasuko;Kondo, Seiji
通讯作者：
Kondo, Seiji