Arsenic salts induced autophagic cell death and hypermethylation of DAPK promoter in SV-40 immortalized human uroepithelial cells
Arsenic salts induced autophagic cell death and hypermethylation of DAPK promoter in SV-40 immortalized human uroepithelial cells
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DOI：
10.1016/j.toxlet.2007.06.006
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发表时间：
2007-08-30
影响因子：
3.5
通讯作者：
Chen, Wan-Tzu
中科院分区：
文献类型：
--
作者：
Chai, Chee-Yin;Huang, Ya-Chun;Chen, Wan-Tzu
砷是一种众所周知的有毒和致癌物质，与各种人类恶性肿瘤有关，包括皮肤癌、肺癌和膀胱癌。特别是，三氧化二砷已成功地用于治疗急性早幼粒细胞白血病患者。此外，砷可诱导恶性肿瘤细胞凋亡或自噬。然而，砷致癌的潜在机制仍不清楚。在这项研究中，我们证明了砷处理的SV-HUC-1细胞中产生的自噬体的增加，通过使用电子显微镜。此外，砷处理后SV-HUC-1细胞中自噬体形成的重要调控因子Beclin- 1蛋白表达呈剂量依赖性增加，甲基化特异性PCR显示，砷处理后SV-HUC-1细胞启动子区CpG位点发生高甲基化，DAPK蛋白表达降低。由于在包括膀胱癌在内的多种恶性肿瘤中发现了由启动子超甲基化引起的肿瘤抑制基因的表观遗传沉默，我们的研究结果为理解砷诱导的尿路上皮细胞癌变机制提供了新的见解。(C)2007爱思唯尔爱尔兰有限公司保留所有权利。
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. (C) 2007 Elsevier Ireland Ltd. All rights reserved.