Effect of a c-Met-specific, ATP-competitive small-molecule inhibitor SU11274 on human ovarian carcinoma cell growth, motility, and invasion
Effect of a c-Met-specific, ATP-competitive small-molecule inhibitor SU11274 on human ovarian carcinoma cell growth, motility, and invasion
复制标题
DOI：
10.1111/j.1525-1438.2007.01135.x
复制
发表时间：
2008-09-01
影响因子：
4.8
通讯作者：
Mok, S. C.
中科院分区：
文献类型：
--
作者：
Koon, E. C.;Ma, P. C.;Mok, S. C.
已显示受体酪氨酸激酶c-Met的表达增加与增强的细胞增殖、运动和侵袭相关。本研究的目的是表征正常和恶性人类卵巢上皮细胞中总的和活化的c-Met表达，并确定抑制c-Met活化对卵巢上皮细胞生长、运动和侵袭的影响。免疫组化结果显示，119例卵巢癌中有82例（68%）c-Met过度表达。定量逆转录-聚合酶链反应和Western blot分析显示，卵巢癌细胞系有较高水平的c-Met信使RNA，总蛋白，和活化蛋白的表达相比，正常卵巢上皮细胞培养物。使用特异性三磷酸腺苷竞争性小分子抑制剂SU 11274，在正常和卵巢癌细胞系中激活的c-Met减少。3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四氮唑（MTT）法显示细胞生长抑制与各细胞系中检测到的活化c-Met水平直接相关（r =-0.87，P = 0.012）。使用改良的Boyden小室分析，与未处理的细胞相比，SU 11274处理的卵巢癌细胞显示出显著降低的细胞运动性和侵袭性（分别为P = 0.003和P < 0.001）。这些数据表明，c-Met在体内和体外的大多数恶性卵巢上皮细胞中过表达，并且降低体外活化的c-Met可以显著降低卵巢癌细胞的生长、运动和侵袭。开发特异性抑制c-Met激活的疗法可能代表了高水平c-Met表达的卵巢癌患者的一种新的治疗方式。
Increased expression of the receptor tyrosine kinase c-Met has been shown to correlate with enhanced cell proliferation, motility, and invasion. The objectives of this study were to characterize total and activated c-Met expression in both normal and malignant human ovarian epithelial cells and to determine the effects of inhibiting the activation of c-Met on ovarian epithelial cell growth, motility, and invasion. Total c-Met was overexpressed in 82 (68%) of 119 ovarian carcinomas, as shown by immunohistochemistry. Quantitative reverse transcription-polymerase chain reaction and Western blot analyses revealed that ovarian carcinoma cell lines had higher levels of c-Met messenger RNA, total protein, and activated protein expression compared to normal ovarian epithelial cell cultures. Using a specific adenosine triphosphate-competitive small-molecule inhibitor, SU11274, activated c-Met was decreased in normal and ovarian carcinoma cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that cell growth inhibition directly correlated to the level of activated c-Met detected in each cell line (r = -0.87, P = 0.012). Using modified Boyden chamber assays, ovarian carcinoma cells treated with SU11274 demonstrated significantly decreased cell motility and invasion compared to untreated cells (P = 0.003 and P < 0.001, respectively). These data indicate that c-Met is overexpressed in the majority of malignant ovarian epithelial cells both in vivo and in vitro and that decreasing activated c-Met in vitro can significantly decrease ovarian carcinoma cell growth, motility, and invasion. Developing therapies that specifically inhibit the activation of c-Met may represent a novel therapeutic modality for patients with ovarian carcinomas expressing high levels of c-Met.