Chen Po-Hung, Lan Cheng-Che E, Chiou Min-Hsi, Hsieh Ming-Chu, Chen Gwo-Shing
Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.
Chem Res Toxicol. 2005 Feb;18(2):139-44. doi: 10.1021/tx049834b.
Inorganic arsenic is an environmental toxin and a human carcinogen. Being a co-mutagen, arsenic enhances carcinogenesis of ultraviolet irradiation on the mouse skin. Apoptosis, a well-regulated cell death process, is essential for cell development and tissue homeostasis. Dysregulation of apoptosis will lead to various kinds of pathological conditions, such as cancers. The purpose of this study is to investigate the apoptotic effect induced by the interactions of arsenic and UVB on cultured human keratinocytes. Cultured keratinocytes were treated with sodium arsenite (1 microM) and/or UVB 50 mJ/cm2 irradiation in different combinations, including arsenic alone (As group), UVB alone (UVB group), arsenic followed by UVB (As/UVB group), and UVB followed by As (UVB/As group) treatments. Our results revealed that a low concentration of sodium arsenite did not induce keratinocytes apoptosis. The UVB group showed obvious elevation of caspase-8, -9, and -3 activities in addition to strong induction of apoptosis as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling (TUNEL) assay. Similar pro-apoptotic effects were observed in the UVB/As group. In contrast, only subtle changes of cell morphology and survival rate were noticed in the As/UVB group. In addition, the results of Western blot and activity assay of caspase-8, -9, and -3 revealed that neither the receptor nor the mitochondrial apoptotic signaling pathway was activated in the As/UVB group. Therefore, we conclude that the pretreatment of keratinocytes with sodium arsenite decreased the pro-apoptotic effects induced by UVB. This finding corroborated with the animal model studying the effects of arsenic and UVB on carcinogenesis. The molecular mechanisms by which arsenic decreased UVB-induced apoptosis remain to be elucidated.
无机砷是一种环境毒素和人类致癌物。作为一种共诱变剂，砷可增强紫外线对小鼠皮肤的致癌作用。细胞凋亡是一种受到良好调控的细胞死亡过程，对细胞发育和组织稳态至关重要。细胞凋亡失调会导致各种病理状况，如癌症。本研究的目的是探讨砷和紫外线B（UVB）相互作用对培养的人角质形成细胞诱导的凋亡效应。用不同组合的亚砷酸钠（1微摩尔）和/或50毫焦/平方厘米的UVB照射处理培养的角质形成细胞，包括单独砷处理（As组）、单独UVB处理（UVB组）、先砷后UVB处理（As/UVB组）和先UVB后砷处理（UVB/As组）。我们的结果显示，低浓度的亚砷酸钠不会诱导角质形成细胞凋亡。UVB组除通过末端脱氧核苷酸转移酶介导的脱氧尿苷缺口末端标记（TUNEL）检测确定有强烈的凋亡诱导外，还显示半胱天冬酶-8、-9和-3活性明显升高。在UVB/As组中观察到类似的促凋亡效应。相比之下，在As/UVB组中仅注意到细胞形态和存活率的细微变化。此外，蛋白质免疫印迹以及半胱天冬酶-8、-9和-3的活性检测结果显示，As/UVB组中受体和线粒体凋亡信号通路均未被激活。因此，我们得出结论，用亚砷酸钠预处理角质形成细胞可降低UVB诱导的促凋亡效应。这一发现与研究砷和UVB对致癌作用影响的动物模型结果相符。砷降低UVB诱导的细胞凋亡的分子机制仍有待阐明。
