...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular cancer therapeutics >Overexpression of DDX43 Mediates MEK Inhibitor Resistance through RAS Upregulation in Uveal Melanoma Cells
【24h】

Overexpression of DDX43 Mediates MEK Inhibitor Resistance through RAS Upregulation in Uveal Melanoma Cells

机译：DDX43的过表达通过葡萄膜黑色素瘤细胞中的RAS上调介导MEK抑制剂抗性。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The majority of uveal melanomas carry oncogenic mutations in the G proteins GNAQ and GNA11, with consequent activation of the MAPK pathway. Selective MEK inhibitors, such as selumetinib, have shown clinical benefit in uveal melanoma. However, mechanisms of drug resistance limit their efficacy in some patients. Analysis of MEK inhibitor-resistant uveal melanoma cell lines revealed the induction of RAS protein expression and activity. This effect was mediated by the RNA helicase DDX43, which was remarkably overexpressed in these cells. Depletion of DDX43 in MEK inhibitor-resistant cells decreased RAS proteins and inhibited ERK and AKT pathways. On the contrary, ectopic expression of DDX43 in parental uveal melanoma cells induced RAS protein levels and rendered cells resistant to MEK inhibition. Similar to DDX43 depletion, downregulation of KRAS, HRAS, and NRAS inhibited downstream pathways in the resistant cells, overcoming mutant GNAQ signaling. We also analyzed the expression of DDX43 in liver metastases of patients with uveal melanoma by RT-PCR, and found a significant overexpression of DDX43 in patients who did not benefit from selumetinib therapy. In conclusion, DDX43 induces RAS protein expression and signaling, mediating a novel mechanism of MEK inhibitor resistance. The detection of DDX43 in patients with uveal melanoma could lead to more targeted therapies for this disease. (C) 2014 AACR.
机译：大多数葡萄膜黑色素瘤在G蛋白GNAQ和GNA11中携带致癌突变，从而激活MAPK途径。选择性MEK抑制剂（如selumetinib）已在葡萄膜黑色素瘤中显示出临床益处。但是，耐药机制限制了它们在某些患者中的疗效。对MEK抑制剂抗葡萄膜黑色素瘤细胞系的分析揭示了RAS蛋白表达和活性的诱导。该作用由RNA解旋酶DDX43介导，该酶在这些细胞中明显过表达。 MEK抑制剂耐药细胞中DDX43的消耗减少了RAS蛋白，并抑制了ERK和AKT途径。相反，DDX43在葡萄膜葡萄膜黑色素瘤细胞中的异位表达可诱导RAS蛋白水平升高，并使细胞对MEK抑制具有抗性。与DDX43耗竭相似，KRAS，HRAS和NRAS的下调抑制了耐药细胞中的下游途径，从而克服了突变GNAQ信号。我们还通过RT-PCR分析了葡萄膜黑色素瘤患者肝转移中DDX43的表达，发现未从selumetinib治疗中受益的DDX43明显过表达。总之，DDX43诱导RAS蛋白表达和信号传导，介导MEK抑制剂抗性的新机制。在葡萄膜黑色素瘤患者中检测DDX43可能导致针对该疾病的更有针对性的治疗。 （C）2014 AACR。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号