Comprehensive gene expression profiles of NK cell neoplasms identify vorinostat as an effective drug candidate
Comprehensive gene expression profiles of NK cell neoplasms identify vorinostat as an effective drug candidate
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DOI：
10.1016/j.canlet.2012.12.022
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发表时间：
2013-06-01
期刊：
影响因子：
9.7
通讯作者：
Seto, Masao
中科院分区：
文献类型：
--
作者：
Karube, Kennosuke;Tsuzuki, Shinobu;Seto, Masao
NK细胞肿瘤是一种具有侵袭性临床病程的淋巴细胞恶性肿瘤。在本研究中，我们分析了NK细胞肿瘤的基因表达谱，并试图找到重要的分子途径和新的有效药物。基因表达谱的通路分析提示JAK-STAT通路、nf - κ B通路和Wnt通路在NK细胞肿瘤中的重要作用。值得注意的是，western blot分析显示，STAT3在NK细胞系中的表达和磷酸化水平高于正常NK细胞或其他细胞系。这些发现表明在NK细胞肿瘤中存在JAK-STAT激活。基因表达谱的连接图（CMAP）分析确定了抗NK细胞肿瘤的候选药物。在CMAP分析建议的药物中，我们重点关注嘌呤霉素、phenoxybenzamine、LY294002、wortmannin、vorinostat和trichostatin A，因为它们具有较高的富集分数。我们将这些药物添加到NK细胞系和其他细胞系中。其中伏立诺他抑制NK细胞系增殖的浓度明显低于其他细胞系。抑制JAM-STAT通路似乎有助于这种效果。伏立诺他可能是一个很好的候选用于治疗NK细胞肿瘤。2013爱思唯尔爱尔兰有限公司版权所有。
NK cell neoplasms are lymphoid malignancies with an aggressive clinical course. In the present study, we analyzed gene expression profiling of NK cell neoplasms and attempted to identify important molecular pathways and new effective drugs. Pathway analysis of gene expression profiles suggested the important roles of the JAK-STAT pathway, NF-kappa B pathway or Wnt pathways in NK cell neoplasms. Notably, western blot analysis revealed that STAT3 was expressed and phosphorylated at a higher level in NK cell lines than in normal NK cells or other cell lines. These findings indicate the occurrence of JAK-STAT activation in NK cell neoplasms. Connectivity Map (CMAP) analysis of gene expression profiles identified candidate drugs against NK cell neoplasms. Among the drugs suggested by CMAP analysis, we focused on puromycin, phenoxybenzamine, LY294002, wortmannin, vorinostat and trichostatin A because they exhibited high enrichment scores. We added these drugs to NK cell lines and other cell lines. Among the drugs, vorinostat suppressed NK cell line proliferation at a significantly lower concentration compared to other cell lines. Suppression of the JAM-STAT pathway appeared to contribute to this effect. Vorinostat may be a good candidate for use in the therapy against NK cell neoplasms. (C) 2013 Elsevier Ireland Ltd. All rights reserved.