Song Li, Zhao Junyu, Jin Xiaoting, Li Zhuoyu, Newton Ian P, Liu Weiping, Xiao Hong, Zhao Meirong
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China; MOE Key Lab of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China.
Toxicol Lett. 2014 Aug 17;229(1):284-91. doi: 10.1016/j.toxlet.2014.06.003. Epub 2014 Jun 23.
Dichlorodiphenyltrichloroethane (DDT), an organochlorine pollutant, is associated with several types of cancer. However, the relationship between DDT and colorectal cancer is uncertain. In this study, the impact of p,p'-DDT on colorectal cancer growth was evaluated using both in vitro and in vivo models. Our results indicated that the proliferation of human colorectal adenocarcinoma DLD1 cells was significantly promoted after exposed to low concentrations of p,p'-DDT ranging from 10(-12) to 10(-7) M for 96 h. Exposure to p,p'-DDT from 10(-10) to 10(-8) M led to upregulation of phospho-GSK3β (Ser9), β-catenin, c-Myc and cyclin D1 in DLD1 cells. RNA interference of β-catenin inhibited the proliferation of DLD1 cells stimulated by p,p'-DDT. Inhibiting of estrogen receptors (ERs) had no significant effect on the action of p,p'-DDT. Treatment with p,p'-DDT induced production of intracellular reactive oxygen species (ROS) and inhibited superoxide dismutase (SOD) activity in DLD1 cells. Treatment with N-acetyl-L-cysteine (NAC), a ROS inhibitor, suppressed the induction of Wnt/β-catenin signaling and DLD1 cell proliferation by p,p'-DDT. Moreover, in a mouse xenograft model, 5 nmol/kg p,p'-DDT resulted in increased tumor size, oxidative stress and Wnt/β-catenin signaling. These results indicated that low concentrations of p,p'-DDT promoted colorectal cancer growth through Wnt/β-catenin signaling, which was mediated by oxidative stress. The finding suggests an association between low concentrations of p,p'-DDT exposure and colorectal cancer progression.
滴滴涕（DDT）是一种有机氯污染物，与多种癌症相关。然而，DDT与结直肠癌之间的关系尚不确定。在本研究中，我们使用体外和体内模型评估了p,p'-DDT对结直肠癌生长的影响。我们的结果表明，人结肠腺癌DLD1细胞在暴露于10(-12)至10(-7) M的低浓度p,p'-DDT 96小时后，其增殖显著促进。暴露于10(-10)至10(-8) M的p,p'-DDT导致DLD1细胞中磷酸化GSK3β（Ser9）、β-连环蛋白、c-Myc和细胞周期蛋白D1上调。β-连环蛋白的RNA干扰抑制了p,p'-DDT刺激的DLD1细胞增殖。抑制雌激素受体（ERs）对p,p'-DDT的作用没有显著影响。用p,p'-DDT处理诱导了DLD1细胞内活性氧（ROS）的产生并抑制了超氧化物歧化酶（SOD）活性。用ROS抑制剂N-乙酰-L-半胱氨酸（NAC）处理可抑制p,p'-DDT对Wnt/β-连环蛋白信号通路的诱导和DLD1细胞增殖。此外，在小鼠异种移植模型中，5 nmol/kg的p,p'-DDT导致肿瘤大小增加、氧化应激和Wnt/β-连环蛋白信号通路增强。这些结果表明，低浓度的p,p'-DDT通过氧化应激介导的Wnt/β-连环蛋白信号通路促进结直肠癌生长。这一发现提示低浓度p,p'-DDT暴露与结直肠癌进展之间存在关联。
