Histone deacetylase inhibitors suppress the inducibility of nuclear factor-kappaB by tumor necrosis factor-alpha receptor-1 down-regulation.
Histone deacetylase inhibitors suppress the inducibility of nuclear factor-kappaB by tumor necrosis factor-alpha receptor-1 down-regulation.
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发表时间：
2006
期刊：
影响因子：
11.2
通讯作者：
G. Imre;V. Gekeler;A. Leja;T. Beckers;M. Boehm
中科院分区：
文献类型：
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作者：
G. Imre;V. Gekeler;A. Leja;T. Beckers;M. Boehm
最近，组蛋白去乙酰化酶（HDAC）酶的抑制引起了肿瘤学界的关注，作为血液和实体肿瘤（包括非小细胞肺癌（NSCLC））的新治疗机会。在血液恶性肿瘤，如弥漫性大B细胞淋巴瘤，HDAC抑制剂（HDI），辛二酰苯胺异羟肟酸（SAHA），最近进入II期和III期临床试验。为了进一步了解它们对肿瘤细胞的作用，我们研究了HDI治疗对NSCLC中核因子-κ B（NF-κ B）通路功能的可能影响。我们发现，在NSCLC细胞系A549和NCI-H460中，NF-κ B通路是强烈诱导的，例如，通过用肿瘤坏死因子-α（TNF-α）刺激。用HDI孵育几种NSCLC细胞系导致TNF-α受体-1的基因表达大大降低。HDI处理的A549和NCI-H460细胞下调TNF-α受体-1 mRNA和蛋白水平以及表面暴露，因此对TNF-α处理的反应是IKK磷酸化和激活减少，IkappaB-α磷酸化延迟，NF-κ B核转位和DNA结合减弱。因此，TNF-α对NF-κ B靶基因表达的刺激强烈降低。此外，我们观察到SAHA对裸鼠上生长的A549异种移植物显示出体内抗肿瘤功效。因此，HDIs可能通过降低肿瘤细胞对TNF-α介导的NF-κ B通路激活的反应性，对肿瘤治疗有好处。这些发现也暗示了HDIs在炎症性疾病中的可能用途，这些疾病与TNF-α的过度产生有关，如类风湿性关节炎或克罗恩病。
Recently, the inhibition of histone deacetylase (HDAC) enzymes has attracted attention in the oncologic community as a new therapeutic opportunity for hematologic and solid tumors including non-small cell lung cancer (NSCLC). In hematologic malignancies, such as diffuse large B-cell lymphoma, the HDAC inhibitor (HDI), suberoylanilide hydroxamic acid (SAHA), has recently entered phase II and III clinical trials. To further advance our understanding of their action on tumor cells, we investigated the possible effect of HDI treatment on the functionality of the nuclear factor-kappaB (NF-kappaB) pathway in NSCLC. We found that in the NSCLC cell lines, A549 and NCI-H460, the NF-kappaB pathway was strongly inducible, for example, by stimulation with tumor necrosis factor-alpha (TNF-alpha). Incubation of several NSCLC cell lines with HDIs resulted in greatly reduced gene expression of TNF-alpha receptor-1. HDI-treated A549 and NCI-H460 cells down-regulated TNF-alpha receptor-1 mRNA and protein levels as well as surface exposure, and consequently responded to TNF-alpha treatment with reduced IKK phosphorylation and activation, delayed IkappaB-alpha phosphorylation, and attenuated NF-kappaB nuclear translocation and DNA binding. Accordingly, stimulation of NF-kappaB target gene expression by TNF-alpha was strongly decreased. In addition, we observed that SAHA displayed antitumor efficacy in vivo against A549 xenografts grown on nude mice. HDIs, therefore, might beneficially contribute to tumor treatment, possibly by reducing the responsiveness of tumor cells to the TNF-alpha-mediated activation of the NF-kappaB pathway. These findings also hint at a possible use of HDIs in inflammatory diseases, which are associated with the overproduction of TNF-alpha, such as rheumatoid arthritis or Crohn's disease.