Inflammatory cytokine COX-2 mediated cell proliferation through increasing cyclin D1 expression induced by inorganic arsenic in SV-HUC-1 human uroepithelial cells

Abstract

Inorganic arsenic is a potent human carcinogen. However, its carcinogenic mechanism remains unknown. The cell cycle progression plays a critical role in tumorigenesis. There are several important cell cycle-associated proteins, such as cyclins and PCNA, which are considered as cellular oncogenes. In this study, we have described the expressions of key proteins regulating cell-cycle progression, and analyzed the effects of PI3K and MAPK/COX-2/PGE2 pathways on cyclin D1 expression. The SV-HUC-1 cell line was treated with NaAsO₂ for 24 h. We found that the viability of arsenite-treated cells decreased significantly at 8 and 10 μM NaAsO₂ concentration and 4 μM NaAsO₂ promoted cell proliferation by increasing bromodeoxyuridine (BrdU) expression. The expressions of cyclin D1 and PCNA, prostaglandin E2 (PGE2) levels and Bcl-2/Bax ratio were increased. ROS levels were increased in a dose-dependent manner. Cyclin D1 over-expression was decreased by MAPK, PI3K and cyclooxygenase-2 (COX-2) inhibitors as well as the free radical scavenger, melatonin. Moreover, PGE2 was regulated by MAPK and PI3K/COX-2 signal pathways. Overall, arsenite induced human uroepithelial cell proliferation by increasing the expressions of cyclin D1 and PCNA. The dysregulation of key factors in the cell cycle was mediated by inflammatory cytokine COX-2 via PI3K and MAPK signal pathways.