Deficiency of Fyn protein is prerequisite for apoptosis induced by Src family kinase inhibitors in human mesothelioma cells
Deficiency of Fyn protein is prerequisite for apoptosis induced by Src family kinase inhibitors in human mesothelioma cells
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DOI：
10.1093/carcin/bgs109
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发表时间：
2012-05-01
期刊：
影响因子：
4.7
通讯作者：
Fujimori, Yoshihiro
中科院分区：
文献类型：
--
作者：
Eguchi, Ryoji;Kubo, Shuji;Fujimori, Yoshihiro
恶性间皮瘤是一种由浆液膜间皮细胞产生的侵袭性肿瘤。Src家族激酶（SFKs）在细胞粘附、增殖、存活和凋亡中具有关键作用。在此，我们检查了SFK抑制剂在NCI-H2052、ACC-MESO-4和NCI-H28细胞、间皮瘤细胞系和Met 5A（一种人非恶性间皮瘤细胞系）中的作用。我们发现，PP 2，一个选择性SFK抑制剂，抑制SFK活性，并诱导凋亡的caspase-8介导的NCI-H28细胞，而不是Met 5A，NCI-H2052和ACC-MESO-4细胞。在这些细胞系中表达SFK成员Src、Yes、Fyn和林恩蛋白，而NCI-H28细胞缺乏Fyn蛋白。针对Fyn的小干扰RNA（siRNA）促进PP 2诱导的NCI-H2052和ACC-MESO-4细胞中caspase-8介导的凋亡。在所有间皮瘤细胞系中，PP 2降低了林恩蛋白水平并抑制了SFK活性。林恩siRNA在NCI-H28细胞中诱导caspase-8活化和凋亡，但在NCI-H2052和ACC-MESO-4细胞中不诱导caspase-8活化和凋亡。然而，在NCI-H2052和ACC-MESO-4细胞中，Fyn和林恩的双RNA干扰敲低诱导凋亡伴随着caspase-8的激活。达沙替尼是一种多酪氨酸激酶（包括SFK）的抑制剂，也可抑制SFK活性，并诱导NCI-H28细胞中林恩蛋白水平降低、caspase-8活化和凋亡，但在其他细胞系中不存在。目前的研究表明，SFK抑制剂诱导caspase-8依赖的细胞凋亡引起的林恩蛋白减少Fyn缺陷间皮瘤细胞。
Malignant mesothelioma is an aggressive tumor arising from mesothelial cells of serous membranes. Src family kinases (SFKs) have a pivotal role in cell adhesion, proliferation, survival and apoptosis. Here, we examined the effect of SFK inhibitors in NCI-H2052, ACC-MESO-4 and NCI-H28 cells, mesothelioma cell lines and Met5A, a human non-malignant mesothelial cell line. We found that PP2, a selective SFK inhibitor, inhibited SFK activity and induced apoptosis mediated by caspase-8 in NCI-H28 but not Met5A, NCI-H2052 and ACC-MESO-4 cells. Src, Yes, Fyn and Lyn protein, which are members of the SFK, were expressed in these cell lines, whereas NCI-H28 cells were deficient in Fyn protein. Small interfering RNA (siRNA) targeting Fyn facilitated PP2-induced apoptosis mediated by caspase-8 in NCI-H2052 and ACC-MESO-4 cells. PP2 reduced Lyn protein levels and suppressed SFK activity in all mesothelioma cell lines. Lyn siRNA induced caspase-8 activation and apoptosis in NCI-H28 cells but not in NCI-H2052 and ACC-MESO-4 cells. However, double RNA interference knockdown of Fyn and Lyn induced apoptosis accompanied by caspase-8 activation in NCI-H2052 and ACC-MESO-4 cells. Dasatinib, an inhibitor of multi-tyrosine kinases including SFK, also inhibited SFK activity and induced reduction of Lyn protein levels, caspase-8 activation and apoptosis in NCI-H28 cells but not in other cell lines. Present study suggests that SFK inhibitors induce caspase-8-dependent apoptosis caused by reduction of Lyn protein in Fyn-deficient mesothelioma cells.