Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
Cancer Lett. 2013 Jun 1;333(1):47-55. doi: 10.1016/j.canlet.2012.12.022. Epub 2013 Jan 21.
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-κB 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 JAK-STAT pathway appeared to contribute to this effect. Vorinostat may be a good candidate for use in the therapy against NK cell neoplasms.
NK 细胞肿瘤是具有侵袭性临床病程的淋巴恶性肿瘤。在本研究中，我们分析了 NK 细胞肿瘤的基因表达谱，并试图鉴定重要的分子途径和新的有效药物。基因表达谱的途径分析表明，JAK-STAT 途径、NF-κB 途径或 Wnt 途径在 NK 细胞肿瘤中具有重要作用。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 JAK-STAT 激活发生在 NK 细胞肿瘤中。基因表达谱的 Connectivity Map (CMAP) 分析确定了针对 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、苯氧苄胺、LY294002、渥曼青霉素、伏立诺他和曲古抑菌素 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。在这些药物中，伏立诺他在明显低于其他细胞系的浓度下抑制 NK 细胞系的增殖。抑制 JAK-STAT 途径似乎对此有贡献。伏立诺他可能是治疗 NK 细胞肿瘤的一个很好的候选药物。
