Autophagy induced by suberoylanilide hydroxamic acid in Hela S3 cells involves inhibition of protein kinase B and up-regulation of Beclin 1
Autophagy induced by suberoylanilide hydroxamic acid in Hela S3 cells involves inhibition of protein kinase B and up-regulation of Beclin 1
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DOI：
10.1016/j.biocel.2007.07.020
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发表时间：
2008-01-01
影响因子：
4
通讯作者：
Gu, Jiang
中科院分区：
文献类型：
--
作者：
Cao, Qi;Yu, Chuanfei;Gu, Jiang
组蛋白去乙酰化酶抑制剂是很有前途的化疗药物，有些已进入临床试验阶段。几种分子机制已被援引来描述其在体内和体外对癌细胞的作用。自噬已被观察到对几种抗癌试剂的反应，并已被证明是细胞死亡的原因。然而，这种现象的确切机制仍然不清楚。在这里，我们证明了辛二酰苯胺异羟肟酸，组蛋白去乙酰化酶抑制剂，诱导非凋亡性细胞死亡与几个特定的自噬特征在Hela S3细胞。琥珀酰苯胺异羟肟酸抑制雷帕霉素的哺乳动物靶标的活性，雷帕霉素是一种大自噬的负调节剂，其以Beclin 1和自噬相关的7依赖性方式诱导自噬体的形成。该过程由Akt和结节性硬化症2介导，如通过连续活性Akt质粒转染和RNA干扰结节性硬化症2的抑制所证明的。我们的数据提供了辛二酰苯胺异羟肟酸通过干扰哺乳动物靶细胞雷帕霉素信号通路诱导Hela S3细胞自噬的第一个证据。这些发现表明辛二酰苯胺异羟肟酸可能通过其特定途径诱导自噬性癌细胞死亡，并邀请进一步研究该途径的详细机制，以探索该化合物作为化疗剂的全部潜力。(c)2007爱思唯尔有限公司保留所有权利。
Histone deacetylase inhibitors are promising chemotherapeutic agents and some are in clinical trials. Several molecular mechanisms have been invoked to describe their effects on cancer cells in vivo and in vitro. Autophagy has been observed in response to several anticancer reagents and has been demonstrated to be responsible for cell death. However, the exact mechanism of this phenomenon is still not clear. Here we demonstrated that suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, induces nonapoptotic cell death with several specific features characteristic of autophagy in Hela S3 cells. Suberoylanilide hydroxamic acid inhibits the activity of the mammalian target of rapamycin, a negative regulator of macroautophagy which induces the formation of autophagosomes in a Beclin 1- and autophagy-related 7-dependent manner. This process is mediated by Akt and tuberous sclerosis 2 as is demonstrated by inhibition by continuous active Akt plasmid transfection and RNA interference of tuberous sclerosis 2. Our data provide the first evidence that suberoylanilide hydroxamic acid induces autophagy in Hela S3 cells through interference with the mammalian target of rapamycin signaling pathway. These findings suggest that suberoylanilide hydroxamic acid may induce autophagic cancer cell death via its specific pathway, and invite further investigation into the detailed mechanism of this pathway to explore this compound's full potential as a chemotherapeutic agent. (c) 2007 Elsevier Ltd. All rights reserved.