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

• Arsenite increased HIF-1α, VEGF, and COX-2 expressions in SV-HUC-1 cells.
• PI3K/AKT and MAPK pathways were involved in HIF-1α, VEGF and COX-2 over-expressions.
• Arsenite-induced ROS were involved in the activation of PI3K and MAPK pathways.

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-1α (HIF-1α), 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 μM) for 24 h. Arsenite-induced HIF-1α, 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-1α expression was only decreased by ERK1/2 inhibitor. It was found that superoxide (O2−) generation was involved in arsenite-induced the activation of MAPK and PI3K pathways, which led to the HIF-1α, COX-2 and VEGF overexpressions. In conclusion, arsenite-induced COX-2, VEGF and HIF-1α expressions, mediated partially by reactive oxygen species (ROS), were regulated by MAPK and PI3K/AKT signaling pathways in human uroepithelial cells.

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