...
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy
【24h】

High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy

机译:他莫昔芬抗性的高通量异位表达筛选可鉴定出一种可阻断自噬的非典型激酶

获取原文
获取原文并翻译 | 示例
           

摘要

Resistance to tamoxifen in breast cancer patients is a serious therapeutic problem and major efforts are underway to understand underlying mechanisms. Resistance can be either intrinsic or acquired. We derived a series of subcloned MCF7 cell lines that were either highly sensitive or naturally resistant to tamoxifen and studied the factors that lead to drug resistance. Gene-expression studies revealed a signature of 67 genes that differentially respond to tamoxifen in sensitive vs. resistant subclones, which also predicts disease-free survival in tamoxifen-treated patients. High-throughput cell-based screens, in which >500 human kinases were independently ectopically expressed, identified 31 kinases that conferred drug resistance on sensitive cells. One of these, HSPB8, was also in the expression signature and, by itself, predicted poor clinical outcome in one cohort of patients. Further studies revealed that HSPB8 protected MCF7 cells from tamoxifen and blocked autophagy. Moreover, silencing HSBP8 induced autophagy and caused cell death. Tamoxifen itself induced autophagy in sensitive cells but not in resistant ones, and tamoxifen-resistant cells were sensitive to the induction of autophagy by other drugs. These results may point to an important role for autophagy in the sensitivity to tamoxifen.
机译:乳腺癌患者对他莫昔芬的耐药性是一个严重的治疗问题,并且正在努力研究其潜在机制。抗性可以是内在的或获得的。我们衍生了一系列对他莫昔芬高度敏感或天然耐药的亚克隆MCF7细胞系,并研究了导致耐药性的因素。基因表达研究揭示了敏感和耐药亚克隆中对他莫昔芬有不同反应的67个基因的特征,这也预测了他莫昔芬治疗患者的无病生存期。高通量的基于细胞的筛选(其中> 500种人类激酶被独立地异位表达)确定了31种赋予敏感细胞耐药性的激酶。其中之一,HSPB8,也具有表达特征,并据其本身预测一组患者的临床结局较差。进一步的研究表明,HSPB8可保护MCF7细胞免受他莫昔芬的侵害并阻止自噬。此外,沉默HSBP8诱导自噬并引起细胞死亡。他莫昔芬本身在敏感细胞中诱导自噬,但在抗性细胞中不诱导,而他莫昔芬抗性细胞对其他药物诱导的自噬敏感。这些结果可能表明自噬在他莫昔芬敏感性中的重要作用。

著录项

  • 来源
  • 作者单位

    The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287,Harvard Institute of Proteomics,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    Harvard Institute of Proteomics,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    The Dana Farber Cancer Institute, Boston,MA 02115;

    Harvard Institute of Proteomics,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287,Harvard Institute of Proteomics,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115,Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Medical Sciences, 71364 Shiraz, Iran;

    Harvard Institute of Proteomics,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    Harvard Institute of Proteomics,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    Harvard Institute of Proteomics,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    Harvard Institute of Proteomics,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287,Harvard Institute of Proteomics,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    functional screen estrogen receptor;

    机译:功能屏|雌激素受体;

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