Critical role of p21 on olaquindox-induced mitochondrial apoptosis and S-phase arrest involves activation of PI3K/AKT and inhibition of Nrf2/H0-1pathway
Critical role of p21 on olaquindox-induced mitochondrial apoptosis and S-phase arrest involves activation of PI3K/AKT and inhibition of Nrf2/H0-1pathway
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DOI：
10.1016/j.fct.2017.07.054
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发表时间：
2017-10-01
影响因子：
4.3
通讯作者：
Tang, Shusheng
中科院分区：
文献类型：
--
作者：
Li, Daowen;Dai, Chongshan;Tang, Shusheng
喹乙醇是一种喹喔啉1，4-二-N-氧化物，被称为抗菌剂和饲料添加剂，用于治疗细菌感染和促进动物生长。然而，潜在的毒性机制仍然未知。本研究旨在探讨p21在喹乙醇诱导人肝癌G2细胞（HepG 2）线粒体凋亡和S期阻滞中的作用机制。结果表明，喹乙醇促进ROS的产生，以非p53依赖的方式抑制p21蛋白的表达，并使p21磷酸化。同时，喹乙醇激活AKT和Nrf 2/HO-1通路，上调Bax/Bcl-2比值，破坏线粒体膜电位（MMP），导致细胞色素c释放和caspase级联激活，最终诱导细胞凋亡。喹乙醇可诱导HepG 2细胞S期阻滞，其机制与Cyclin A、Cyclin E和CDK 2表达增加有关。p21基因敲除可降低细胞活力，增强氧化应激，加重olaquindox诱导的线粒体凋亡和S期阻滞，参与激活PI 3 K/AKT和抑制Nrf 2/HO-1通路。PI 3 K/AKT抑制剂（LY 294002）和HO抑制剂（ZnPP-IX）均能增加olaquindox诱导的细胞凋亡和S期阻滞。总之，p21基因敲低可通过进一步激活PI 3 K/AKT和抑制Nrf 2/HO-1通路，增加喹乙醇诱导的线粒体凋亡和S期阻滞。我们的研究为喹乙醇的分子机制提供了新的见解，并阐明了p21的作用。(C)2017爱思唯尔有限公司版权所有
Olaquindox, a quinoxaline 1,4-di-N-oxide, is known as an antibacterial agent and feed additive to treat bacterial infections and promote animal growth. However, the potential mechanism of toxicity is still unknown. The present study aims to explore the molecular mechanism of p21 on olaquindox-induced mitochondrial apoptosis and S-phase arrest in human hepatoma G2 cells (HepG2). As a result, olaquindox promoted production of ROS, suppressed the protein expression p21 in p53-independent way and phosphorylated p21. Meanwhile, olaquindox activated AKT and Nrf2/HO-1 pathway, up-regulated Bax/Bcl-2 ratio, disrupted mitochondrial membrane potential (MMP) and subsequently caused cytochrome c release and a cascade activation of caspase, eventually induced apoptosis. Olaquindox could induce S-phase arrest in HepG2 cells involved with the increase of Cyclin A, Cyclin E and CDK 2. Furthermore, knockdown of p21 decreased cell viability, enhanced oxidative stress, aggravated olaquindox-induced mitochondrial.apoptosis and S-phase arrest involvement of activating PI3K/AKT and inhibiting Nrf2/HO-1 pathway. PI3K/AKT inhibitor (LY294002) and HO-linhibitor (ZnPP-IX) both increased olaquindox-induced apoptosis and S-phase arrest. In conclusion, knockdown of p21 increased olaquindox-induced mitochondrial apoptosis and S-phase arrest through further activating PI3K/AKT and inhibiting Nrf2/HO-1pathway. Our study provided new insights into the molecular mechanism of olaquindox and shed light on the role of p21. (C) 2017 Elsevier Ltd. All rights reserved.