Arsenite sensitizes human melanomas to apoptosis via tumor necrosis factor α-mediated pathway
Arsenite sensitizes human melanomas to apoptosis via tumor necrosis factor α-mediated pathway
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DOI：
10.1074/jbc.m314131200
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发表时间：
2004-05-21
影响因子：
4.8
通讯作者：
Hei, TK
中科院分区：
文献类型：
--
作者：
Ivanov, VN;Hei, TK
砷是一种公认的人类致癌物质，与包括皮肤癌在内的多种癌症有关。奇怪的是，砷也被用于治疗白血病，尽管是低剂量的，已经有超过世纪的历史了。在这里，我们证明，低至中等浓度的亚砷酸盐（2 - 10 μ M），对正常黑素细胞几乎没有或没有影响，可能会诱导人类黑色素瘤，包括高转移性的细胞凋亡，尽管他们的表面Fas水平低。砷处理后黑色素瘤的凋亡反应的两个先决条件是低核NF-κ B活性和肿瘤坏死因子α的内源性表达。在这些条件下，黑色素瘤细胞获得对肿瘤坏死因子α介导的杀伤的敏感性。另一方面，包括磷脂酰肌醇3-激酶- AKT、MEK-ERK和JNK的信号通路在黑色素瘤细胞中对砷诱导的氧化应激和凋亡起保护作用。这些途径的抑制显著加速亚砷酸盐诱导的细胞凋亡。综上所述，这些数据可以提供潜在的方法，敏化黑色素瘤的细胞毒性作用的亚砷酸盐通过调节信号通路。
Arsenic is a well established human carcinogen and is associated with a variety of cancers including those of the skin. Paradoxically, arsenic has also been used, amid at low doses, in the treatment of leukemia for over a century. Here we demonstrate that low to moderate concentrations of arsenite ( 2 - 10 muM) that has little or no effect on normal melanocytes may induce apoptosis of human melanomas including highly metastatic ones despite their low surface Fas levels. The two prerequisites that dictate apoptotic response of melanomas upon arsenite treatment are low nuclear NF-kappaB activity and an endogenous expression of tumor necrosis factor alpha. Under these conditions, melanoma cells acquired sensitivity to tumor necrosis factor alpha- mediated killing. On the other hand, signaling pathways including those of phosphatidylinositol 3- kinase- AKT, MEK- ERK, and JNK play a protective role against arsenite- induced oxidative stress and apoptosis in melanoma cells. Suppression of these pathways dramatically accelerates arsenite- induced apoptosis. Taken together, these data could provide potential approaches to sensitize melanomas to the cytotoxic effects of arsenite through modulating the signaling pathways.