Furazolidone induces apoptosis through activating reactive oxygen species-dependent mitochondrial signaling pathway and suppressing PI3K/Akt signaling pathway in HepG2 cells
Furazolidone induces apoptosis through activating reactive oxygen species-dependent mitochondrial signaling pathway and suppressing PI3K/Akt signaling pathway in HepG2 cells
复制标题
呋喃唑酮通过激活活性氧依赖性线粒体信号通路并抑制 PI3K/Akt 信号通路诱导 HepG2 细胞凋亡
DOI：
10.1016/j.fct.2014.11.019
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发表时间：
2015-01-01
影响因子：
4.3
通讯作者：
Xiao, Xilong
中科院分区：
文献类型：
--
作者：
Deng, Sijun;Tang, Shusheng;Xiao, Xilong
呋喃唑酮 (FZD) 是一种具有广谱抗菌活性的合成硝基呋喃，已被证明对多种类型的细胞具有遗传毒性和潜在致癌性。然而，FZD 毒性的正确分子机制仍不清楚。本研究旨在探讨FZD对HepG2细胞凋亡的影响，并揭示FZD细胞毒性的信号通路。结果表明，FZD 以剂量依赖性方式诱导 HepG2 细胞凋亡，其特征是细胞核形态变化、细胞膜磷脂酰丝氨酸易位、聚（ADP-核糖）聚合酶（PARP）裂解以及 caspase-9 和 -3 的级联激活。 FZD 可以增强活性氧 (ROS) 的产生，上调 Bax/Bcl-2 比率，破坏线粒体膜电位 (MMP)，随后导致细胞色素 c 释放。 ROS 清除剂（N-乙酰半胱氨酸，NAC）和 caspase 抑制剂均可抑制 FZD 诱导的细胞凋亡。此外，NAC 还可减弱 FZD 诱导的 ROS 生成和线粒体功能障碍。同时，FZD 处理抑制 Akt 的激活和表达，PI3K/Akt 抑制剂 LY294002 促进 FZD 诱导的细胞凋亡。相反，PI3K/Akt 激活剂胰岛素样生长因子-1 (IGF-1) 减弱了 FZD 对 HepG2 细胞的杀伤力。总之，首次证明FZD诱导的HepG2细胞凋亡可能通过ROS依赖性线粒体信号通路介导，并涉及PI3K/Akt信号传导。 (C) 2014 Elsevier Ltd. 保留所有权利。
Furazolidone (FZD), a synthetic nitrofuran with a broad spectrum of antimicrobial activities, has been shown to be genotoxic and potentially carcinogenic in several types of cells. However, the proper molecular mechanisms of FZD toxicity remain unclear. This study was aimed to explore the effect of FZD on apoptosis in HepG2 cells and uncover signaling pathway underlying the cytotoxicity of FZD. The results showed that FZD induced apoptosis in HepG2 cells in a dose-dependent manner characterized by nuclei morphology changes, cell membrane phosphatidylserine translocation, poly (ADP-ribose) polymerase (PARP) cleavage and a cascade activation of caspase-9 and -3. FZD could enhance reactive oxygen species (ROS) generation, up-regulate Bax/BcI-2 ratio, disrupt mitochondrial membrane potential (MMP) and subsequently cause cytochrome c release. Both ROS scavenger (N-acetyl cysteine, NAC) and caspase inhibitors suppressed FZD-induced apoptosis. Furthermore, NAC attenuated FZD-induced ROS generation and mitochondrial dysfunction. Meanwhile, FZD treatment inhibited both the activation and expression of Akt, and PI3K/Akt inhibitor LY294002 promoted FZD-induced apoptosis. On the contrary, PI3K/Akt activator insulin-like growth factor-1 (IGF-1) attenuated lethality of FZD in HepG2 cells. In conclusion, it is first demonstrated that FZD-induced apoptosis in HepG2 cells might be mediated through ROS-dependent mitochondrial signaling pathway and involves PI3K/Akt signaling. (C) 2014 Elsevier Ltd. All rights reserved.