Cadmium induces caspase-independent apoptosis in liver Hep3B cells:: Role for calcium in signaling oxidative stress-related impairment of mitochondria and relocation of endonuclease G and apoptosis-inducing factor
Cadmium induces caspase-independent apoptosis in liver Hep3B cells:: Role for calcium in signaling oxidative stress-related impairment of mitochondria and relocation of endonuclease G and apoptosis-inducing factor
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DOI：
10.1016/j.freeradbiomed.2004.03.020
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发表时间：
2004-06-15
影响因子：
7.4
通讯作者：
Vernhet, L
中科院分区：
文献类型：
--
作者：
Lemarié, A;Lagadic-Gossmann, D;Vernhet, L
镉诱导的细胞毒性与坏死和/或半胱天冬酶依赖性细胞凋亡有关。在本研究中，我们发现，接触镉后，人肝癌 Hep3B 细胞会发生与内切酶 G 和凋亡诱导因子（两种线粒体凋亡蛋白）的核转位相关的不依赖于 caspase 的细胞凋亡。这些蛋白质的释放可能与钙诱导的线粒体稳态改变有关。事实上，首先是细胞质钙的快速持续增加，然后线粒体膜电位和活性氧的产生同时减少。 Bapta-AM（5, 5'-二甲基-双（邻氨基苯氧基）乙烷-N,N,N',N'-四乙酸的乙酰氧基甲酯）是一种钙螯合剂，可阻断所有这些事件并防止镉诱导的细胞凋亡。钌红和鱼藤酮（两种线粒体抑制剂）以及二亚苯基碘鎓（一种黄素蛋白抑制剂）可以抑制活性氧的产生，这也可以防止线粒体膜电位的损失和细胞凋亡。此外，Bapta-AM 和二亚苯基碘鎓几乎完全阻断镉处理细胞中线粒体抗凋亡核因子 kappaB 调节的 bcl-x(L) 蛋白表达的下降。综上所述，我们的结果表明，镉主要通过钙应激和氧化应激相关的线粒体损伤来诱导 Hep3B 细胞凋亡，这可能有利于凋亡诱导因子和核酸内切酶 G 的释放。(C) 2004 Elsevier Inc. 保留所有权利。
Cadmium-induced cellular toxicity has been related to necrosis and/or caspase-dependent apoptosis. In the present study, we show that, on cadmium exposure, the human hepatocarcinoma Hep3B cells undergo caspase-independent apoptosis associated with nuclear translocation of endonuclease G and apoptosis-inducing factor, two mitochondrial apoptogenic proteins. Release of these proteins is likely related to calcium-induced alteration of mitochondrial homeostasis. Indeed, it was first preceded by a rapid and sustained increase in cytoplasmic calcium and then by a coincident loss in mitochondrial membrane potential and production of reactive oxygen species. Bapta-AM (acetoxymethyl ester of 5, 5'-dimethyl-bis (o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), a calcium chelator, blocked all these events and prevented cadmium-induced apoptosis. Production of reactive oxygen species was inhibited by ruthenium red and rotenone, two mitochondrial inhibitors, and by diphenyleneiodonium, a flavoprotein inhibitor, which also prevented both loss in mitochondrial membrane potential and apoptosis. In addition, Bapta-AM and diphenyleneiodonium were found to almost totally block decreased expression of the mitochondrial anti-apoptotic nuclear factor-kappaB-regulated bcl-x(L) protein in cadmium-treated cells. Taken together, our results show that cadmium induces Hep3B cells apoptosis mainly by calcium- and oxidative stress-related impairment of mitochondria, which probably favors release of apoptosis-inducing factor and endonuclease G. (C) 2004 Elsevier Inc. All rights reserved.