Glutathione-related systems and modulation of extracellular signal-regulated kinases are involved in the resistance of AGS adenocarcinoma gastric cells to diallyl disulfide-induced apoptosis
Glutathione-related systems and modulation of extracellular signal-regulated kinases are involved in the resistance of AGS adenocarcinoma gastric cells to diallyl disulfide-induced apoptosis
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DOI：
10.1158/0008-5472.can-05-3067
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发表时间：
2005-12-15
期刊：
影响因子：
11.2
通讯作者：
Ciriolo, MR
中科院分区：
文献类型：
--
作者：
Filomeni, G;Aquilano, K;Ciriolo, MR
我们以前的特点是二烯丙基二硫化物（DADS）对神经母细胞瘤细胞的细胞毒性作用，我们已经显示了一个早期和大量的活性氧产生的c-Jun NH 2-末端激酶介导的凋亡途径的诱导中的关键作用。在目前的工作中，我们报告说，DADS是无效的，在人胃腺癌细胞系（AGS）诱导凋亡。特别是，我们表明，AGS细胞能够恢复从p53/p21介导的细胞周期停滞在G（2）-M期后，DADS治疗，而不会提交细胞死亡。该事件最有可能是由于这些细胞的特殊存活途径，包括：（a）还原型谷胱甘肽（GSH）和蛋白质硫醇之间形成混合二硫化物，（B）较高的诱导型谷胱甘肽过氧化物酶活性，和/或（c）有效调节细胞外信号调节激酶1和2（ERK 1/2）的磷酸化活性水平。此外，通过增加谷胱甘肽过氧化物酶表达或GSH浓度，细胞周期停滞被完全废除;通过降低细胞内GSH的可用性或抑制ERK 1/2的再活化诱导凋亡性死亡。总之，我们的数据表明，ERK 1/2参与AGS细胞的活跃增殖，有效的活性氧缓冲系统使这些细胞抵抗DADS介导的有害作用。
We have previously characterized the cytotoxic action of diallyl disulfide (DADS) on neuroblastoma Cells, and we have shown the crucial role of an early and massive reactive oxygen species production in the induction of c-Jun NH2-terminal kinase-mediated apoptotic pathway. In the present work, we report that DADS is ineffective in inducing apoptosis in a human adenocarcinoma gastric cell line (AGS). In particular, we show that AGS cells are able to recover from the p53/p21-mediated cell cycle arrest in the G(2)-M phase upon DADS treatment, without committing cells to death. This event is most likely due to a peculiar surviving pathway of these cells involving: (a) the formation of mixed disulfides between reduced glutathione (GSH) and protein thiols, (b) a higher and inducible glutathione peroxidase activity, and/or (c) an efficient modulation of the phospho-active levels of the extracellular signal-regulated kinases 1 and 2 (ERK 1/2). Moreover, by increasing glutathione peroxidase expression or GSH concentrations, cell cycle arrest is fully abolished; the apoptotic death is induced by either decreasing the availability of intracellular GSH or inhibiting the reactivation of ERK 1/2. Altogether, our data show that ERK 1/2 participates in the active proliferation of AGS cells and that an efficient reactive oxygen species buffering system makes these cells resistant to DADS-mediated detrimental effects.