...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular cancer therapeutics >Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells.
【24h】

Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells.

机译：使用panobinostat的治疗可在乳腺癌细胞中诱导葡萄糖调节的蛋白78乙酰化和内质网应激。

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

Increased levels of misfolded polypeptides in the endoplasmic reticulum (ER) triggers the dissociation of glucose-regulated protein 78 (GRP78) from the three transmembrane ER-stress mediators, i.e., protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol-requiring enzyme 1alpha, which results in the adaptive unfolded protein response (UPR). In the present studies, we determined that histone deacetylase-6 (HDAC6) binds and deacetylates GRP78. Following treatment with the pan-histone deacetylase inhibitor panobinostat (Novartis Pharmaceuticals), or knockdown of HDAC6 by short hairpin RNA, GRP78 is acetylated in 11 lysine residues, which dissociates GRP78 from PERK. This is associated with the activation of a lethal UPR in human breast cancer cells. Coimmunoprecipitation studies showed that binding of HDAC6 to GRP78 requires the second catalytic and COOH-terminal BUZ domains of HDAC6. Treatment with panobinostat increased the levels of phosphorylated-eukaryotic translation initiation factor (p-eIF2alpha), ATF4, and CAAT/enhancer binding protein homologous protein (CHOP). Panobinostat treatment also increased the proapoptotic BIK, BIM, BAX, and BAK levels, as well as increased the activity of caspase-7. Knockdown of GRP78 sensitized MCF-7 cells to bortezomib and panobinostat-induced UPR and cell death. These findings indicate that enforced acetylation and decreased binding of GRP78 to PERK is mechanistically linked to panobinostat-induced UPR and cell death of breast cancer cells. Mol Cancer Ther; 9(4); 942-52. (c)2010 AACR.
机译：内质网（ER）中错误折叠多肽水平的升高会触发葡萄糖调节蛋白78（GRP78）从三种跨膜ER应激介质（即蛋白激酶RNA样ER激酶（PERK））解离，从而激活转录因子6（ATF6）和需要肌醇的酶1alpha，导致适应性未折叠蛋白反应（UPR）。在本研究中，我们确定组蛋白脱乙酰基酶6（HDAC6）结合并脱乙酰基GRP78。用泛组蛋白脱乙酰基酶抑制剂panobinostat（Novartis Pharmaceuticals）处理或通过短发夹RNA敲低HDAC6后，GRP78在11个赖氨酸残基中被乙酰化，从而使GRP78与PERK分离。这与人类乳腺癌细胞中致命UPR的激活有关。免疫共沉淀研究表明，HDAC6与GRP78的结合需要HDAC6的第二个催化和COOH末端的BUZ域。使用panobinostat的治疗会增加磷酸化真核翻译起始因子（p-eIF2alpha），ATF4和CAAT /增强子结合蛋白同源蛋白（CHOP）的水平。 Panobinostat治疗还可增加促凋亡的BIK，BIM，BAX和BAK水平，并增加caspase-7的活性。降低GRP78可使MCF-7细胞对硼替佐米和panobinostat诱导的UPR和细胞死亡敏感。这些发现表明，增强的乙酰化作用和GRP78与PERK的结合减少与panobinostat诱导的UPR和乳腺癌细胞死亡在机理上存在联系。分子癌疗法; 9（4）; 942-52。 （c）2010年美国机管学会（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