...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Oncogene >Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis
【24h】

Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis

机译：癌细胞的保守特征决定了它们对HAMLET诱导的死亡的敏感性。 c-Myc和糖酵解

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

摘要

HAMLET is the first member of a new family of tumoricidal protein鈥搇ipid complexes that kill cancer cells broadly, while sparing healthy, differentiated cells. Many and diverse tumor cell types are sensitive to the lethal effect, suggesting that HAMLET identifies and activates conserved death pathways in cancer cells. Here, we investigated the molecular basis for the difference in sensitivity between cancer cells and healthy cells. Using a combination of small-hairpin RNA (shRNA) inhibition, proteomic and metabolomic technology, we identified the c-Myc oncogene as one essential determinant of HAMLET sensitivity. Increased c-Myc expression levels promoted sensitivity to HAMLET and shRNA knockdown of c-Myc suppressed the lethal response, suggesting that oncogenic transformation with c-Myc creates a HAMLET-sensitive phenotype. Furthermore, HAMLET sensitivity was modified by the glycolytic state of tumor cells. Glucose deprivation sensitized tumor cells to HAMLET-induced cell death and in the shRNA screen, hexokinase 1 (HK1), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 and hypoxia-inducible factor 1伪 modified HAMLET sensitivity. HK1 was shown to bind HAMLET in a protein array containing 鈭?/span>8000 targets, and HK activity decreased within 15鈥塵in of HAMLET treatment, before morphological signs of tumor cell death. In parallel, HAMLET triggered rapid metabolic paralysis in carcinoma cells. Tumor cells were also shown to contain large amounts of oleic acid and its derivatives already after 15鈥塵in. The results identify HAMLET as a novel anti-cancer agent that kills tumor cells by exploiting unifying features of cancer cells such as oncogene addiction or the Warburg effect.
机译：HAMLET是新的杀虫蛋白-脂质复合物家族的第一个成员，该复合物可广泛杀死癌细胞，同时保留健康的分化细胞。许多不同类型的肿瘤细胞对致死作用敏感，表明HAMLET可以识别并激活癌细胞中保守的死亡途径。在这里，我们研究了癌细胞与健康细胞之间敏感性差异的分子基础。使用小发夹RNA（shRNA）抑制，蛋白质组学和代谢组学技术的组合，我们确定c-Myc癌基因是HAMLET敏感性的重要决定因素。 c-Myc表达水平的提高促进了对HAMLET的敏感性，而c-Myc的shRNA敲低抑制了致死反应，表明c-Myc的致癌转化产生了HAMLET敏感表型。此外，HAMLET敏感性被肿瘤细胞的糖酵解状态所修饰。葡萄糖剥夺使肿瘤细胞对HAMLET诱导的细胞死亡敏感，在shRNA筛选中，己糖激酶1（HK1），6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶1和低氧诱导因子1α修饰了HAMLET敏感性。显示HK1结合含有鈭？/ span> 8000个靶标的蛋白质阵列中的HAMLET，在肿瘤细胞死亡的形态学标志之前，HK活性在HAMLET处理的15'尘埃内下降。同时，HAMLET触发了癌细胞的快速代谢麻痹。还显示了在15'尘埃后，肿瘤细胞已经含有大量的油酸及其衍生物。研究结果表明，HAMLET是一种新型的抗癌药，可通过利用癌细胞的统一特征（如癌基因成瘾或Warburg效应）杀死肿瘤细胞。

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