<i>p, p′</i>-Dichlorodiphenyldichloroethylene Induces Colorectal Adenocarcinoma Cell Proliferation through Oxidative Stress

<div><p><i>p, p′</i>-Dichlorodiphenyldichloroethylene (DDE), the major metabolite of Dichlorodiphenyltrichloroethane (DDT), is an organochlorine pollutant and associated with cancer progression. The present study investigated the possible effects of <i>p,p′</i>-DDE on colorectal cancer and the involved molecular mechanism. The results indicated that exposure to low concentrations of <i>p,p′</i>-DDE from 10⁻¹⁰ to 10⁻⁷M for 96 h markedly enhanced proliferations of human colorectal adenocarcinoma cell lines. Moreover, <i>p,p′</i>-DDE exposure could activate Wnt/β-catenin and Hedgehog/Gli1 signaling cascades, and the expression level of c-Myc and cyclin D1 was significantly increased. Consistently, <i>p,p′</i>-DDE-induced cell proliferation along with upregulated c-Myc and cyclin D1 were impeded by β-catenin siRNA or Gli1 siRNA. In addition, <i>p,p′</i>-DDE was able to activate NADPH oxidase, generate reactive oxygen species (ROS) and reduce GSH content, superoxide dismutase (SOD) and calatase (CAT) activities. Treatment with antioxidants prevented <i>p,p′</i>-DDE-induced cell proliferation and signaling pathways of Wnt/β-catenin and Hedgehog/Gli1. These results indicated that <i>p,p′</i>-DDE promoted colorectal cancer cell proliferation through Wnt/β-catenin and Hedgehog/Gli1 signalings mediated by oxidative stress. The finding suggests an association between <i>p,p′</i>-DDE exposure and the risk of colorectal cancer progression.</p>