title: β-catenin involvement in arsenite-induced VEGF expression in neuroblastoma SH-SY5Y cells.
abstract: Arsenic is a widespread contaminant in the environment especially in drinking water. Although it is a known carcinogen in human, the mechanism by which arsenic induces carcinogenesis is not well understood. Among several effects of arsenic, it has been suggested that arsenic-induced vascular endothelial growth factor (VEGF) expression plays a critical role in arsenic carcinogenesis. In the present study, we demonstrated that arsenite induced VEGF expression in neuroblastoma SH-SY5Y cells without induction of HIF-1α, a well-known transcriptional activator for VEGF suggesting that arsenite-induced VEGF expression in SH-SY5Y cells may not require HIF-1α activation. It has been reported that VEGF expression is regulated by multiple transcription factors including β-catenin. We therefore investigated whether β-catenin was involved in arsenite-induced VEGF expression in SH-SY5Y cells. Treatment of arsenite caused β-catenin accumulation in the nucleus. Additionally, arsenite treatment decreased the activity of GSK3, an enzyme that phosphorylates and targets β-catenin for degradation by proteasome, without activation of its upstream kinase, Akt. Inhibition of PI3K/Akt which negatively regulates GSK3 activity by LY294002 resulted in a decrease in arsenite-mediated β-catenin nuclear accumulation, and VEGF expression. These results suggested that β-catenin plays a role in arsenite-induced VEGF in SH-SY5Y cells, and the induction of β-catenin by arsenite is mediated by inhibition of GSK3 without activating its upstream kinase Akt.
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Rd, Bangkok 10210, Thailand; Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Office of the Higher Education Commission, Thailand.
authors.forename: Piyajit
authors.initials: P
authors.lastname: Watcharasit
authors.forename: Sumitra
authors.initials: S
authors.lastname: Suntararuks
authors.forename: Daranee
authors.initials: D
authors.lastname: Visitnonthachai
authors.forename: Apinya
authors.initials: A
authors.lastname: Thiantanawat
authors.forename: Jutamaad
authors.initials: J
authors.lastname: Satayavivad
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D018053:Arsenites; C495270:CTNNB1 protein, human; D002867:Chromones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009025:Morpholines; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C015001:arsenite