...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular and Cellular Biology >A Synthetic Lethal Interaction between Glutathione Synthesis and Mitochondrial Reactive Oxygen Species Provides a Tumor-Specific Vulnerability Dependent on STAT3
【24h】

A Synthetic Lethal Interaction between Glutathione Synthesis and Mitochondrial Reactive Oxygen Species Provides a Tumor-Specific Vulnerability Dependent on STAT3

机译：谷胱甘肽合成与线粒体活性氧物种之间的合成致命相互作用提供了取决于STAT3的特定于肿瘤的脆弱性

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Increased production of mitochondrion-derived reactive oxygen species (ROS) is characteristic of a metabolic shift observed during malignant transformation. While the exact sources and roles of ROS in tumorigenesis remain to be defined, it has become clear that maintaining redox balance is critical for cancer cell proliferation and survival and, as such, may represent a vulnerability that can be exploited therapeutically. STAT3, a latent cytosolic transcription factor activated by diverse cytokines and growth factors, has been shown to exhibit an additional, nontranscriptional function in mitochondria, including modulation of electron transport chain activity. In particular, malignant transformation by Ras oncogenes exploits mitochondrial STAT3 functions. We used mass spectrometry-based metabolomics profiling to explore the biochemical basis for the STAT3 dependence of Ras transformation. We identified the gamma-glutamyl cycle, the production of glutathione, and the regulation of ROS as a mitochondrion-STAT3-dependent pathway in Ras-transformed cells. Experimental inhibition of key enzymes in the glutathione cycle resulted in the depletion of glutathione, accumulation of ROS, oxidative DNA damage, and cell death in an oncogenic Ras- and mitochondrial STAT3-dependent manner. These data uncover a synthetic lethal interaction involving glutathione production and mitochondrial ROS regulation in Ras-transformed cells that is governed by mitochondrial STAT3 and might be exploited therapeutically.
机译：线粒体来源的活性氧（ROS）产量增加​​是恶性转化过程中观察到的代谢转移的特征。尽管ROS在肿瘤发生中的确切来源和作用尚待确定，但已经清楚的是，维持氧化还原平衡对于癌细胞的增殖和存活至关重要，因此，它可能代表可以被治疗利用的脆弱性。 STAT3是一种由多种细胞因子和生长因子激活的潜在胞质转录因子，已显示在线粒体中具有额外的非转录功能，包括电子转运链活性的调节。特别地，Ras癌基因的恶性转化利用了线粒体STAT3功能。我们使用基于质谱的代谢组学分析来探索Ras转化对STAT3的依赖的生化基础。我们确定了γ-谷氨酰胺循环，谷胱甘肽的生产和ROS的调节作为Ras转化细胞中的线粒体STAT3依赖途径。谷胱甘肽循环中关键酶的实验抑制导致谷胱甘肽耗竭，ROS积累，氧化性DNA损伤以及致癌的Ras和线粒体STAT3依赖性细胞死亡。这些数据揭示了由线粒体STAT3调控的Ras转化细胞中涉及谷胱甘肽产生和线粒体ROS调节的合成致死相互作用，可能在治疗上得到利用。

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