Arsenic induces the expressions of angiogenesis-related factors through PI3K and MAPK pathways in SV-HUC-1 human uroepithelial cells

Arsenic, a well-established human carcinogen, can cause various types of cancers, including bladder cancer. Angiogenesis is a key event for tumor initiation. In this study, several important angiogenesis related factors, including cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1 alpha), were up-regulated and PI3K/AKT and MAPK signal pathways were activated in human uroepithelial cell line (SV-HUC-1) treated with NaAsO2 (0, 1, 2, 4, 8 or 10 mu M) for 24 h. Arsenite-induced HIF-1 alpha, VEGF and COX-2 expressions were decreased by PI3K inhibitors. Blockage of the ERK1/2, p38 and JNK down-regulated the VEGF level, while ERK1/2 and p38 inhibitors were more effective than JNK in attenuating arsenite-induced COX-2 expression. HIF-1 alpha expression was only decreased by ERK1/2 inhibitor. It was found that superoxide (O-2(center dot-)) generation was involved in arsenite-induced the activation of MAPK and PI3K pathways, which led to the HIF-1 alpha, COX-2 and VEGF overexpressions. In conclusion, arsenite-induced COX-2, VEGF and HIF-1 alpha expressions, mediated partially by reactive oxygen species (ROS), were regulated by MAPK and PI3K/AKT signaling pathways in human uroepithelial cells. (C) 2013 Elsevier Ireland Ltd. All rights reserved.