Molecular mechanism of violacein-mediated human leukemia cell death
Molecular mechanism of violacein-mediated human leukemia cell death
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DOI：
10.1182/blood-2004-02-0594
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发表时间：
2004-09-01
期刊：
影响因子：
20.3
通讯作者：
Peppelenbosch, MP
中科院分区：
文献类型：
--
作者：
Ferreira, CV;Bos, CL;Peppelenbosch, MP
紫罗兰素是一种从亚马逊河紫罗兰色杆菌中分离出来的色素，具有多种生物学特性，并因其抗白血病活性而引起人们的兴趣。阐明介导这种活性的分子机制将为理解其对未转化细胞的细胞生理学的影响并考虑其可能的临床应用提供进一步的相关信息。在这里，我们发现紫罗兰素会导致 HL60 白血病细胞凋亡，但在其他类型的白血病细胞或正常人淋巴细胞和单核细胞中对此无效。 Violacein 对 HL60 细胞的细胞毒性发生在 caspase 8 激活、核因子 kappaB (NF-kappaB) 靶基因转录和 p38 丝裂原激活蛋白 (MAP) 激酶激活之前。因此，紫罗兰素的作用类似于这些细胞中的肿瘤坏死因子α（TNF-α）信号转导。因此，英夫利昔单抗（一种拮抗 TNF-α 诱导信号传导的抗体）消除了紫罗兰素的生物活性。此外，紫罗兰素直接激活 TNF 受体 1 信号传导，因为在免疫共沉淀实验中观察到 TNF 受体相关因子 2 (TRAF2) 与该 TNF 受体存在紫罗兰素依赖性关联。因此，violacein 代表了一类新型细胞毒性药物的第一个成员，该药物通过特异性激活 TNF 受体 1 介导 HL60 细胞凋亡。 (C) 2004 年，美国血液学会。
Violacein, a pigment isolated from Chromobacterium violaceum in the Amazon River, presents diverse biologic properties and attracts interest as a consequence of its antileukemic activity. Elucidation of the molecular mechanism mediating this activity will provide further relevant information for understanding its effects on the cellular physiology of untransformed cells and for considering its possible clinical application. Here, we show that violacein causes apoptosis in HL60 leukemic cells but is ineffective in this respect in other types of leukemia cells or in normal human lymphocytes and monocytes. Violacein cytotoxicity in HL60 cells was preceded by activation of caspase 8, transcription of nuclear factor kappaB (NF-kappaB) target genes, and p38 mitogen-activated protein (MAP) kinase activation. Thus, violacein effects resemble tumor necrosis factor alpha (TNF-alpha) signal transduction in these cells. Accordingly, infliximab, an antibody that antagonizes TNF-alpha-induced signaling abolished the biologic activity of violacein. Moreover, violacein directly activated TNF receptor 1 signaling, because a violacein-dependent association of TNF receptor-associated factor 2 (TRAF2) to this TNF receptor was observed in coimmunoprecipitation experiments. Hence, violacein represents the first member of a novel class of cytotoxic drugs mediating apoptosis of HL60 cells by way of the specific activation of TNF receptor 1. (C) 2004 by The American Society of Hematology.