Chronic NaAsO2 exposure promotes migration and invasion of prostate cancer cells by Akt/GSK-3β/β-catenin/TCF4 axis-mediated epithelial-mesenchymal transition

Inorganic arsenic is a Class I human Carcinogen. However, the role of chronic inorganic arsenic exposure on prostate cancer metastasis still unclear. This study aimed to investigate the effect and mechanism of chronic NaAsO ₂ exposure on migration and invasion of prostate cancer cells. DU145 and PC-3 cells were exposed to NaAsO ₂ (2 µmol/L) for 25 generations. Wound healing and Transwell assays showed that chronic NaAsO ₂ exposure promoted migration and invasion of DU145 and PC-3 cells. In addition, chronic NaAsO ₂ exposure induced epithelial-mesenchymal transition (EMT) of DU145 cells by promoting β-catenin/TCF4 transcriptional activity. Mechanically, NaAsO ₂ promoted GSK-3β inactivation in the "disruption complex" through Akt mediated phosphorylation at serine 9, and then inhibited phosphorylation and ubiquitination degradation of β-catenin, leading to β-catenin nuclear translocation. Ly204002, a selective phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor, suppressed the β-catenin/TCF4 complex activation and EMT through blocking the Akt-mediated GSK-3β inactivation in the "disruption complex" in chronic NaAsO ₂ exposed DU145 and PC-3 cells. Moreover, Ly204002 alleviated chronic NaAsO ₂ -induced migration and invasion in DU145 and PC-3 cells. These findings provide evidence that chronic arsenic exposure promoted migration and invasion of prostate cancer cells through inducing EMT driven by AKT/GSK-3β/β-catenin/TCF4 signaling axis. Akt is expected to be a potential therapeutic target for chronic arsenic exposure-mediated prostate cancer metastasis.