Daunorubicin activates NF kappa B and induces kappa B-dependent gene expression in HL-60 promyelocytic and Jurkat T lymphoma cells
Daunorubicin activates NF kappa B and induces kappa B-dependent gene expression in HL-60 promyelocytic and Jurkat T lymphoma cells
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DOI：
10.1074/jbc.272.20.12952
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发表时间：
1997-05-16
影响因子：
4.8
通讯作者：
ONeill, LAJ
中科院分区：
文献类型：
--
作者：
Boland, MP;Foster, SJ;ONeill, LAJ
蒽环类抗生素柔红霉素可以诱导细胞中的程序性细胞死亡（细胞凋亡），最近的研究表明该事件是由神经酰胺通过增强神经酰胺合酶活性介导的，由于神经酰胺的生成与转录因子 NF kappa B 的激活直接相关，因此将其作为柔红霉素作用的新靶点进行研究。在这里，我们描述了如何用柔红霉素治疗 HL-60 早幼粒细胞和 Jurkat T 淋巴瘤细胞柔红霉素导致转录因子 NF kappa B 的激活。柔红霉素的作用在 1-2 小时处理后就很明显，这与细胞因子、肿瘤坏死因子获得的激活时间过程相反，其中 NF kappa B 激活在细胞刺激后几分钟内即可检测到。激活的复合物显示出主要包含 p50 和 p65/RelA 亚基成分，柔红霉素还诱导 I kappa B 降解并增加NF kappa B 连锁报告基因。此外，该药物被发现能强烈增强肿瘤坏死因子诱导 NF kappa B 连锁报告基因的能力，表明这两种药物在这种反应中具有协同作用。这些事件对铁螯合剂甲磺酸去铁胺（去铁胺）以及抗氧化剂和金属螯合剂吡咯烷二硫代氨基甲酸盐敏感。米托蒽醌是一种结构相关的化合物，与柔红霉素不同，它无法经历细胞中的氧化还原循环，也以吡咯烷二硫代氨基甲酸酯敏感的方式激活 NF kappa B。神经酰胺合酶的特异性抑制剂伏马菌素 B1，在先前报道的可阻断该药物诱导的细胞凋亡的浓度范围内，对柔红霉素诱导的 NF kappa B 激活没有影响。然而，除了阻断被激活的 HL-60 细胞的神经酰胺合酶活性外，该药物还可以抑制柔红霉素诱导的神经酰胺增加。因此，这些数据表明，柔红霉素对 NF kappa B 的作用不太可能涉及神经酰胺，但可能涉及内源性细胞过程而不是药物还原代谢产生的活性氧。由于 NF kappa B 可能涉及细胞凋亡，因此这种作用可能是细胞对该药物反应的一个重要方面。
The anthracycline antibiotic, daunorubicin, can induce programmed cell death (apoptosis) in cells, Recent work suggests that this event is mediated by ceramide via enhanced ceramide synthase activity, Since the generation of ceramide has been directly linked with the activation of the transcription factor, NF kappa B, this was investigated as a novel target for the action of daunorubicin, Here we describe how treatment of HL-60 promyelocytes and Jurkat T lymphoma cells with daunorubicin results in the activation of the transcription factor NF kappa B. The effect of daunorubicin was evident following 1-2 h treatment, which was in contrast to the time course of activation obtained with the cytokine, tumor necrosis factor, where NF kappa B activation was detected within minutes of cellular stimulation, Activated complexes were shown to contain predominantly p50 and p65/RelA subunit components, Daunorubicin also induced I kappa B degradation and increased the expression of an NF kappa B linked reporter gene. In addition, the drug was found to strongly potentiate the ability of tumor necrosis factor to induce an NF kappa B-linked reporter gene, suggesting a synergy between these two agents in this response, These events were sensitive to the iron chelator, deferoxamine mesylate (desferal), and the anti-oxidant and metal chelator pyrrolidine dithiocarbamate, A structurally related compound, mitoxantrone, which, unlike daunorubicin, is unable to undergo redox cycling in cells, also activated NF kappa B in a pyrrolidine dithiocarbamate-sensitive manner, A specific inhibitor of ceramide synthase, fumonisin B1, had no effect on daunorubicin induced NF kappa B activation at a range of concentrations previously reported to block apoptosis induced by this drug, However, this agent could inhibit increases in ceramide induced by daunorubicin, in addition to blocking ceramide synthase activity from HL-60 cells which was activated in response to daunorubicin treatment, These data therefore suggest that the effect of daunorubicin on NF kappa B is unlikely to involve ceramide, but may involve reactive oxygen species generated as a result of endogenous cellular processes rather than reductive metabolism of the drug, As NF kappa B may be involved in apoptosis, this effect may be an important aspect of the cellular responses to this agent.