Rapamycin resistance is linked to defective regulation of Skp2.
Rapamycin resistance is linked to defective regulation of Skp2.
复制标题
DOI：
10.1158/0008-5472.can-11-2195
复制
发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Marks AR
中科院分区：
文献类型：
--
作者：
Totary-Jain H;Sanoudou D;Dautriche CN;Schneller H;Zambrana L;Marks AR
哺乳动物雷帕霉素靶蛋白（mTOR）在控制恶性细胞生长中起作用。目前正在癌症试验中评估包括雷帕霉素（西罗莫司）在内的mTOR抑制剂。然而，大量肿瘤对雷帕霉素具有耐药性。在这项研究中，我们报告了雷帕霉素下调Skp2（泛素蛋白连接酶复合物的一个亚基）的能力，确定了对雷帕霉素敏感的肿瘤。RNAi介导的人肿瘤细胞Skp2的沉默增加了它们对雷帕霉素的体外敏感性，并抑制了体内肿瘤异种移植物的生长。我们的研究结果表明，Skp2水平是对mTOR抑制剂的抗肿瘤反应的关键决定因素，突出了一个潜在的重要药物基因组学标记，以预测对雷帕霉素的敏感性以及Skp2沉默策略用于治疗目的。
The mammalian target of rapamycin (mTOR) plays a role in controlling malignant cellular growth. mTOR inhibitors including rapamycin (sirolimus) are currently being evaluated in cancer trials. However, a significant number of tumors are rapamycin resistant. In this study, we report that the ability of rapamycin to down-regulate Skp2, a subunit of the ubiquitin protein ligase complex, identifies tumors that are sensitive to rapamycin. RNAi-mediated silencing of Skp2 in human tumor cells increased their sensitivity to rapamycin in vitro and inhibited the growth of tumor xenografts in vivo. Our findings suggest that Skp2 levels are a key determinant of antitumor responses to mTOR inhibitors, highlighting a potentially important pharmacogenomic marker to predict sensitivity to rapamycin as well as Skp2 silencing strategies for therapeutic purposes.