P21waf1/ciP1 plays a critical role in furazolidone-induced apoptosis in HepG2 cells through influencing the caspase-3 activation and ROS generation
P21waf1/ciP1 plays a critical role in furazolidone-induced apoptosis in HepG2 cells through influencing the caspase-3 activation and ROS generation
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P21(Waf1/Cip1)通过影响caspase-3的激活和ROS的产生，在呋喃唑酮诱导的HepG2细胞凋亡中发挥关键作用。
DOI：
10.1016/j.fct.2015.12.004
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发表时间：
2016-02-01
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硝基呋喃类化合物，在体外实验中表现出明显的遗传毒性和细胞毒性，但其具体机制尚不清楚。P21（Waf 1/CiP 1）（p21）是一种细胞周期蛋白依赖性激酶，在DNA损伤后细胞周期阻滞和凋亡中起重要作用。本研究旨在探讨p21在FZD诱导HepG 2细胞凋亡中的作用及其可能机制。首先，我们证明了FZD（50 μ g/mL）处理增加了p21的mRNA水平，但通过缩短其半衰期降低了p21的蛋白水平。FZD抑制PI 3 K/Akt信号通路的作用与p21的降解有关。p21蛋白表达的改变调节了FZD诱导的细胞凋亡。p21的过表达减弱了FZD诱导的caspase-3激活和ROS产生，最终减少了细胞凋亡。相反，通过siRNA敲低p21增强FZD诱导的这些现象。此外，p21对FZD诱导的ROS产生的影响可能与Nrf 2/HO-1通路有关，Nrf 2/HO-1通路是氧化应激防御反应的关键调节因子。总之，这些结果表明，p21通过影响caspase-3激活和ROS产生在FZD诱导的HepG 2细胞凋亡中起关键作用。(C)2015爱思唯尔有限公司版权所有。
Furazolidone (FZD), a synthetic nitrofuran with a broad spectrum of antimicrobial activities, has been shown to exhibit marked genotoxity and cytotoxicity in vitro, but the proper mechanism was unclear. P21(Waf1/CiP1) (p21), a cyclin-dependent kinase, is critically involved in cell cycle arrest and apoptosis in response to DNA injury. This study was aimed to explore the role of p21 in FZD-induced apoptosis in HepG2 cells and uncover its possible mechanism. Firstly, we demonstrated that FZD (50 mu g/mL) treatment increased the mRNA level of p21 but reduced the protein level of p21 by shortening its half-life. Moreover, the degradation of p21 was associated with the inhibition of PI3K/Akt pathway by FZD. Then, the change of p21 protein expression modulated FZD-induced apoptosis. Overexpression of p21 attenuated FZD-induced caspase-3 activation and ROS generation, eventually reduced apoptosis. Conversely, knockdown of p21 by siRNA enhanced FZD-induced those phenomenon. In addition, the influence of p21 on FZD-induced ROS generation might be associated with Nrf2/HO-1 pathway which was a key regulator in defense response against oxidative stress. In conclusion, these findings demonstrated that p21 plays a critical role in FZD-induced apoptosis in HepG2 cells through influencing the caspase-3 activation and ROS generation. (C) 2015 Elsevier Ltd. All rights reserved.