Oxidative DNA damage is involved in ochratoxin A-induced G2 arrest through ataxia telangiectasia-mutated (ATM) pathways in human gastric epithelium GES-1 cells in vitro
Oxidative DNA damage is involved in ochratoxin A-induced G2 arrest through ataxia telangiectasia-mutated (ATM) pathways in human gastric epithelium GES-1 cells in vitro
复制标题
体外人胃上皮 GES-1 细胞中氧化 DNA 损伤参与赭曲霉毒素 A 通过共济失调毛细血管扩张突变 (ATM) 途径诱导的 G2 期阻滞
DOI：
10.1007/s00204-013-1043-3
复制
发表时间：
2013-10-01
影响因子：
6.1
通讯作者：
Zhang, Xianghong
中科院分区：
文献类型：
--
作者：
Cui, Jinfeng;Liu, Jing;Zhang, Xianghong
Ochratoxin A (OTA), one of the most abundant mycotoxin food contaminants, is classified as "possibly carcinogenic to humans." Our previous study showed that OTA could induce a G(2) arrest in immortalized human gastric epithelium cells (GES-1). To explore the putative roles of oxidative DNA damage and the ataxia telangiectasia-mutated (ATM) pathways on the OTA-induced G(2) arrest, the current study systematically evaluated the roles of reactive oxygen species (ROS) production, DNA damage, and ATM-dependent pathway activation on the OTA-induced G(2) phase arrest in GES-1 cells. The results showed that OTA exposure elevated intracellular ROS production, which directly induced DNA damage and increased the levels of 8-OHdG and DNA double-strand breaks (DSBs). In addition, it was found that OTA treatment induced the phosphorylation of the ATM protein, as well as its downstream molecules Chk2 and p53, in response to DNA DSBs. Inhibition of ATM by the pharmacological inhibitor caffeine or siRNA effectively prevented the activation of ATM-dependent pathways and rescued the G(2) arrest elicited by OTA. Finally, pretreatment with the antioxidant N-acetyl-l-cysteine (NAC) reduced the OTA-induced DNA DSBs, ATM phosphorylation, and G(2) arrest. In conclusion, the results of this study suggested that OTA-induced oxidative DNA damage triggered the ATM-dependent pathways, which ultimately elicited a G(2) arrest in GES-1 cells.
