Atrazine promotes cholangiocarcinoma cell proliferation and migration via GPER-mediated PI3K/Akt/NF-κB pathway

Atrazine (ATZ), an herbicide widely distributed on a global scale, possess a potential risk for the development of various cancers upon environmental exposure. However, the effect and molecular mechanism of ATZ in cholangiocarcinoma (CCA), is still unclear. This study aimed to investigate the effect of ATZ on the proliferation and migration of CCA cell in vitro. Immortalized human cholangiocytes (MMNK-1) and three CCA cell lines (KKU-055, KKU-100 and KKU-213B) were treated with 0.01 to 100 μM of ATZ and 17β-estradiol (E2). The results showed that, similar to E2, low doses (0.01 to 1 μM) of ATZ promoted the proliferation of all CCA and MMNK-1 cells. ATZ exposure increased non-genomic G protein-coupled estrogen receptor (GPER) expression in the cell membrane and cytoplasm of KKU-213B and KKU-055 cells via G2/M cell cycle accumulation. This, in turn, promoted the proliferation and migration of CCA cells. ATZ exposure induced the upregulation of GPER and increased expression levels of PI3K, p-PI3K, Akt, p-Akt, NF-κB and PCNA. In contrast, following ATZ treatment, the GPER antagonist G15 significantly downregulated the GPER/PI3K/Akt/NF-κB pathway. These results suggest that ATZ promotes CCA cell proliferation and migration through the GPER/PI3K/Akt/NF-κB pathway. This information can enhance public health awareness regarding ATZ contamination to prevent the relative risk of CCA.