Noma Kazuhiro, Naomoto Yoshio, Gunduz Mehmet, Matsuoka Junji, Yamatsuji Tomoki, Shirakawa Yasuhiro, Nobuhisa Tetsuji, Okawa Takaomi, Takaoka Munenori, Tomono Yasuko, Hiroyuki Ohmori, Gunduz Esra, Tanaka Noriaki
Department of Gastroenterological Surgery, Okayama University, 2-5-1 Shikata-cho, Okayamashi 700-8558, Japan.
Oncol Rep. 2005 Sep;14(3):645-50.
Mutations of proto-oncogene c-kit in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. However, no study has been published concerning the effects of imatinib on GIST cells with various types of KIT mutation. To investigate the effects of imatinib on various c-kit mutations found in GISTs, cell proliferation and apoptosis assays were performed in two GIST cell lines with different KIT mutations. One of the cell lines, GIST-T1, revealed a heterozygous deletion of exon 11 in the c-kit, while the other cell line, GIST882, possessed a homozygous missense mutation of exon 13 in the c-kit gene. Imatinib inhibited proliferation and induced apoptosis in both cell lines. Imatinib potently suppressed proliferation of the GIST882 cell line at the concentration of 1.0 microM, whereas it inhibited the GIST-T1 at 0.1 microM. In two types of activating mutant KIT, imatinib could inhibit the constitutive activation of both types of KIT mutant, although the antiproliferative effect on GIST882 was weaker than on GIST-T1. Western blot analysis revealed that apoptosis related proteins were activated or suppressed by imatinib in both cell lines in the respective manner. Our results suggest that the apoptotic signal trans-duction caused by imatinib in GISTs is susceptible to various types of KIT mutation.
胃肠道间质瘤（GISTs）中原癌基因c-kit的突变被认为会导致KIT的组成性激活，这与其肿瘤发生有关。伊马替尼因其对KIT激酶活性的抑制作用而对GISTs具有治疗潜力。然而，尚未有关于伊马替尼对具有各种类型KIT突变的GIST细胞影响的研究发表。为了研究伊马替尼对GISTs中发现的各种c-kit突变的影响，在两种具有不同KIT突变的GIST细胞系中进行了细胞增殖和凋亡检测。其中一个细胞系GIST-T1显示c-kit外显子11杂合缺失，而另一个细胞系GIST882在c-kit基因中具有外显子13的纯合错义突变。伊马替尼在两种细胞系中均抑制增殖并诱导凋亡。伊马替尼在浓度为1.0 microM时能有效抑制GIST882细胞系的增殖，而在0.1 microM时抑制GIST-T1细胞系。在两种激活型突变KIT中，伊马替尼可以抑制两种类型KIT突变体的组成性激活，尽管其对GIST882的抗增殖作用比对GIST-T1弱。蛋白质印迹分析表明，凋亡相关蛋白在两种细胞系中均以各自的方式被伊马替尼激活或抑制。我们的结果表明，伊马替尼在GISTs中引起的凋亡信号转导对各种类型的KIT突变敏感。
