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

Abstract

Abstract 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 NaAsO2 exposure on migration and invasion of prostate cancer cells. DU145 and PC-3 cells were exposed to NaAsO2 (2 µmol/L) for 25 generations. Wound healing and Transwell assays showed that chronic NaAsO2 exposure promoted migration and invasion of DU145 and PC-3 cells. In addition, chronic NaAsO2 exposure induced epithelial-mesenchymal transition (EMT) of DU145 cells by promoting β-catenin/TCF4 transcriptional activity. Mechanically, NaAsO2 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 NaAsO2 exposed DU145 and PC-3 cells. Moreover, Ly204002 alleviated chronic NaAsO2-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.