Expression of STAT3 and Bcl-6 oncoprotein in sodium arsenite-treated SV-40 immortalized human uroepithelial cells.
Arsenic is widely distributed in the environment, and it is a proven toxic and carcinogenic agent. On the southwest coast of Taiwan, an endemic occurrence of chronic arsenical poisoning due to a high concentration of arsenic in artesian-well water has been reported. However, the mechanisms of its carcinogenic action are still unclear. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is an essential cascade for mediating normal functions of different cytokines in the development of the hematopoietic and immune systems. In this study, the substantial morphological changes observed in SV-40 immortalized human uroepithelial cells (SV-HUC-1) after treatment of various concentrations of arsenite were examined, and the expression of Bcl-6, Jak-2 and p-STAT3 (Tyr 705) were evaluated by immunocytochemistry and Western blotting. Our results showed that the expression of Bcl-6 increased dose-dependently in arsenite-treated urothelial cells. Sodium arsenite treatment reduced Jak-2 protein expression in a dose-dependent manner. However, treatment of SV-HUC-1 cells with arsenite at concentration ranges from 2 and 4microM for 48h dramatically increased p-STAT3 (Tyr 705), but the levels decreased at 8-40microM of arsenite. Our data suggest that arsenic-mediated inactivation of the JAK-STAT signaling pathway might be caused by Bcl-6 interaction with JAK tyrosine kinase or STAT. In conclusion, our findings indicate that arsenic inhibits JAK tyrosine kinase protein expression and suggest the interference in the JAK-STAT pathway might be through Bcl-6 playing an important role in arsenic-associated carcinogenesis.
Huang
Ya-Chun
YC
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Hung
Wen-Chun
WC
Kang
Wan-Yi
WY
Chen
Wan-Tzu
WT
Chai
Chee-Yin
CY
D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D002461:Cell Line, Transformed; D048430:Cell Shape / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000378:metabolism*; D010766:Phosphorylation; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013539:Simian virus 40; D017670:Sodium Compounds / Q000633:toxicity*; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D018053:Arsenites; C084103:BCL6 protein, human; D002273:Carcinogens; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017670:Sodium Compounds; C017947:sodium arsenite; C507924:JAK2 protein, human; D053614:Janus Kinase 2