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

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• 作者：Jinfeng Cui (1)
  Jing Liu (2)
  Sha Wu (2)
  Yuan Wang (2)
  Haitao Shen (2)
  Lingxiao Xing (2)
  Junling Wang (2)
  Xia Yan (2)
  Xianghong Zhang (1)
  
• 关键词：Ochratoxin A ; G2 arrest ; DNA damage ; Ataxia telangiectasia mutated ; Oxidative stress
• 刊名：Archives of Toxicology
• 出版年：2013
• 出版时间：October 2013
• 年：2013
• 卷：87
• 期：10
• 页码：1829-1840
• 全文大小：
• 作者单位：Jinfeng Cui (1)
  Jing Liu (2)
  Sha Wu (2)
  Yuan Wang (2)
  Haitao Shen (2)
  Lingxiao Xing (2)
  Junling Wang (2)
  Xia Yan (2)
  Xianghong Zhang (1)
  
  1. Department of Pathology, The Second Hospital, Hebei Medical University, No. 215, Heping Western Road, Shijiazhuang, Hebei, People’s Republic of China
  2. Laboratory of Pathology, Hebei Medical University, No. 361, Zhongshan Eastern Road, Shijiazhuang, Hebei, People’s Republic of China
  
• ISSN：1432-0738

文摘

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 G2 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 G2 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 G2 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 G2 arrest elicited by OTA. Finally, pretreatment with the antioxidant N-acetyl-l-cysteine (NAC) reduced the OTA-induced DNA DSBs, ATM phosphorylation, and G2 arrest. In conclusion, the results of this study suggested that OTA-induced oxidative DNA damage triggered the ATM-dependent pathways, which ultimately elicited a G2 arrest in GES-1 cells.