...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Synthetic lethal metabolic targeting of cellular senescence in cancer therapy
【24h】

Synthetic lethal metabolic targeting of cellular senescence in cancer therapy

机译：癌症治疗中细胞衰老的合成致死代谢靶向。

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

Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimeth)iation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eμ-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TlS-competent lymphomas but not TIS-incompetent Suv39h1~-lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.
机译：激活的癌基因和抗癌化学疗法可诱导细胞衰老，这是活细胞的终末生长停滞，其特征在于S期进入阻滞组蛋白3赖氨酸9甲基化（H3K9me3）。尽管治疗诱导的衰老（TIS）改善了长期结果，但衰老肿瘤细胞的潜在有害特性使其定量消除成为治疗的重点。在这里，我们使用EIS-myc转基因小鼠淋巴瘤模型，其中TIS依赖于H3K9组蛋白甲基转移酶Suv39h1，以显示体内和体外衰老相关代谢重编程的机制和治疗方法。诱导衰老的化疗后，具有TlS能力的淋巴瘤而非具有TIS能力的Suv39h1-淋巴瘤显示出更高的葡萄糖利用率和更高的ATP产生。我们证明这与大量的蛋白毒性应激有关，这是先前描述的衰老相关分泌表型（SASP）的结果。产生SASP的TIS细胞表现出内质网应激，未折叠的蛋白应答（UPR）和泛素化增加，从而以有毒的能量消耗方式将有毒蛋白靶向自噬。因此，TIS淋巴瘤与缺乏强SASP反应的衰老模型不同，对阻断葡萄糖的利用或自噬更为敏感，这导致它们通过caspase-12和caspase-3介导的内质网相关凋亡而被选择性清除。因此，这些代谢需求在体内对TIS诱导的药理靶向可促进肿瘤消退并进一步改善治疗效果。这些发现揭示了TIS的高分解代谢性质，可通过合成致死代谢靶向进行治疗。

著录项

  • 来源
    《Nature》 |2013年第7467期|421-425|共5页
  • 作者

    Jan R. Doerr; Yong Yu; Maja Milano vie; Gregor Beuster; Christin Zasada; J. Henry M. Daebritz; Jan Lisec; Dido Lenze; Anne Gerhardt; Katharina Schleicher; Susanne Kratzat; Bettina Purfuerst; Stefan Walenta; Wolfgang Mueller-Klieser; Markus Graeler; Michael Hummel; Ulrich Keller; Andreas K. Buck; Bernd Doerken; Lothar Wilhnitzer; Maurice Reimann; Stefan Kempa; Soyoung Lee; Clemens A. Schmitt;

  • 作者单位

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany;

    Max-Delbrueck-CenterforMolecularMedicine(MDC), Robert-Roessle-Strasse 10,13125 Berlin, Germany;

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany;

    Max-Delbrueck-CenterforMolecularMedicine(MDC), Robert-Roessle-Strasse 10,13125 Berlin, Germany;

    Integrative Metabolomics and Proteomics, Berlin Institute of Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10,13125 Berlin, Germany;

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany;

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany,German Cancer Consortium, Deutsches Krebsforschungzentrum (DKFZ), Im Neuenheimer Feld 280,69120 Heidelberg, Germany;

    Charite-Universitaetsmedizin Berlin, Department of Pathology, Chariteplatz 1, Berlin 10117, Germany;

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany;

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany;

    Technische Universitaet Muenchen, Ⅲ Medical Department, Ismaninger Strasse 22,81675 Munich, Germany;

    Max-Delbrueck-CenterforMolecularMedicine(MDC), Robert-Roessle-Strasse 10,13125 Berlin, Germany;

    Universitaetsmedizin der Johannes Gutenberg-Universitaet, Institute of Physiology and Pathophysiology, Duesbergweg 6,55128 Mainz, Germany;

    Universitaetsmedizin der Johannes Gutenberg-Universitaet, Institute of Physiology and Pathophysiology, Duesbergweg 6,55128 Mainz, Germany;

    Universitaetsklinikum Jena, Department of Anesthesiology and Intensive Care Medicine & Center for Sepsis Control and Care (CSCC), Erlanger Allee 1,07747 Jena, Germany;

    Charite-Universitaetsmedizin Berlin, Department of Pathology, Chariteplatz 1, Berlin 10117, Germany;

    Technische Universitaet Muenchen, Ⅲ Medical Department, Ismaninger Strasse 22,81675 Munich, Germany;

    Universitaetsklinikum Wuerzburg, Department of Nuclear Medicine, Oberduerrbacher Strasse 6,97080 Wuerzburg, Germany;

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany,Max-Delbrueck-CenterforMolecularMedicine(MDC), Robert-Roessle-Strasse 10,13125 Berlin, Germany;

    Max Planck Institute of Molecular Plant Physiology, Am Muehlenberg 1,14476 Potsdam, Germany;

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany;

    Integrative Metabolomics and Proteomics, Berlin Institute of Medical Systems Biology, Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10,13125 Berlin, Germany;

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany,Max-Delbrueck-CenterforMolecularMedicine(MDC), Robert-Roessle-Strasse 10,13125 Berlin, Germany;

    Charite-Universitaetsmedizin Berlin, MolekularesKrebsforschungszentrum(MKFZ),AugustenburgerPlatz 1,13353 Berlin,Germany,Max-Delbrueck-CenterforMolecularMedicine(MDC), Robert-Roessle-Strasse 10,13125 Berlin, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);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

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