Arsenic salts induced autophagic cell death and hypermethylation of DAPK promoter in SV-40 immortalized human uroepithelial cells.
Arsenic is a well-known toxic and carcinogenic agent, and associated with various human malignancies, including skin, lung and bladder cancers. Paradoxically, arsenic trioxide has been used successfully in the treatment of patients with acute promyelocytic leukemia. In addition, arsenic could induce cell apoptosis or autophagy in malignant cells. However, the underlying mechanism of arsenic-induced carcinogenesis is still unclear. In this study, we demonstrated an increase of autophagosomes was produced in arsenic-treated SV-HUC-1 cells by using electron microscopy. In addition, increase of Beclin-1, an important regulator for the formation of autophagosome, protein expression in a dose-dependent manner was also found. By using methylation specific PCR, we revealed hypermethylation of CpG sites in the promoter region with decreased DAPK protein expression in arsenic-treated SV-HUC-1 cells. As epigenetic silencing of tumor suppressor genes by promoter hypermethylation has been found in a variety of malignancies including bladder cancer, our results provide new insights for the understanding of the mechanism of arsenic-induced carcinogenesis in urothelial cells.
Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. cychai@kmu.edu.tw
Chee-Yin
CY
Chai
Ya-Chun
YC
Huang
Wen-Chun
WC
Hung
Wan-Yi
WY
Kang
Wan-Tzu
WT
Chen
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D018053:Arsenites / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002472:Cell Transformation, Viral; D018899:CpG Islands / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D064550:Death-Associated Protein Kinases; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D013539:Simian virus 40; D017670:Sodium Compounds / Q000633:toxicity*; D015854:Up-Regulation; D019459:Urothelium / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure
D051017:Apoptosis Regulatory Proteins; D018053:Arsenites; C491997:BECN1 protein, human; D000071186:Beclin-1; D002273:Carcinogens; D008565:Membrane Proteins; D017670:Sodium Compounds; C017947:sodium arsenite; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases