Methyl methanesulfonate induces apoptosis in p53-deficient H1299 and Hep3B cells through a caspase 2-and mitochondria-associated pathway
Methyl methanesulfonate induces apoptosis in p53-deficient H1299 and Hep3B cells through a caspase 2-and mitochondria-associated pathway
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甲磺酸甲酯通过 caspase 2 和线粒体相关途径诱导 p53 缺陷的 H1299 和 Hep3B 细胞凋亡
DOI：
10.1016/j.etap.2012.09.019
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发表时间：
2012-11-01
影响因子：
4.3
通讯作者：
Yang, Jun
中科院分区：
文献类型：
--
作者：
Jiang, Ying;Zhang, Xiao-Yun;Yang, Jun
甲磺酸甲酯 (MMS) 已被证明可通过 p53 依赖性途径诱导各种细胞类型凋亡。然而，p53 功能的药理学和遗传阻断导致对 MMS 治疗的相似或延迟敏感性，表明存在不依赖于 p53 的细胞凋亡机制。为了了解 MMS 诱导细胞凋亡过程中涉及的 p53 独立机制，我们使用 p53 缺陷的 H1299 和 Hep3B 细胞建立了 MMS 诱导的细胞凋亡模型。我们的结果表明，浓度为 50、100、200、400 和 800 μM 的 MMS 诱导 gammaH2AX 灶的形成，而浓度较高（400 和 800 μM）的 MMS 处理导致两种细胞系凋亡。这种凋亡性细胞死亡与线粒体膜电位的丧失、活性 caspase 2 的核胞质转位、线粒体中细胞色素 c 的释放以及 caspase 9、caspase 3 和 PARP 的裂解同时发生。然而，MMS 诱导的 DNA 损伤未能稳定 p53 家族成员 TAp73 和 DNp73。这些结果证明了 MMS 诱导细胞凋亡的独立于 p53 和 p73 的机制，涉及活性 caspase 2 的核胞质转位以及线粒体介导的途径。 (C) 2012 Elsevier B.V. 保留所有权利。
Methyl methanesulfonate (MMS) has been shown to induce apoptosis in various cell types through p53-dependent pathways. Nevertheless, pharmacological and genetic blockade of p53 functions results in similar or delayed sensitivity to MMS treatment, suggesting the presence of p53-independent apoptotic mechanisms. To understand the p53-independent mechanisms that are engaged during MMS-induced apoptosis, we established MMS-induced apoptotic cell models using p53-deficient H1299 and Hep3B cells. Our results demonstrated that MMS at concentrations of 50, 100, 200, 400 and 800 mu M induced the formation of gammaH2AX foci, and that at higher concentrations, 400 and 800 mu M, MMS treatment led to apoptosis in the two cell lines. This apoptotic cell death was concurrent with the loss of mitochondrial membrane potential, nuclear-cytosolic translocation of active caspase 2, release of cytochrome c from mitochondria, and the cleavage of caspase 9, caspase 3 and PARP. However, MMS-induced DNA damage failed to stabilize the p53 family members TAp73 and DNp73. These results demonstrated a p53- and p73-independent mechanism for MMS-induced apoptosis that involves the nuclear-cytosolic translocation of active caspase 2 as well as the mitochondria-mediated pathway. (C) 2012 Elsevier B.V. All rights reserved.