Journal
TOXICOLOGY LETTERS
Volume 222, Issue 3, Pages 303-311Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2013.08.008
Keywords
Arsenite; HIF-1 alpha; COX-2; VEGF; MAPK; PI3K/AKT
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Funding
- National Natural Science Foundation of China (NSFC) [81072244, 30771865]
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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.
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