• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>Cell Death Disease >Constitutive localization of DR4 in lipid rafts is mandatory for TRAIL-induced apoptosis in B-cell hematologic malignancies
【2h】

Constitutive localization of DR4 in lipid rafts is mandatory for TRAIL-induced apoptosis in B-cell hematologic malignancies

机译：在TRAIL诱导的B细胞血液系统恶性肿瘤细胞凋亡中DR4在脂质筏中的组成性定位是必不可少的

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) acts as an apoptosis inducer for cancer cells sparing non-tumor cell targets. However, several phase I/II clinical trials have shown limited benefits of this molecule. In the present work, we investigated whether cell susceptibility to TRAIL ligation could be due to the presence of TRAIL death receptors (DRs) 4 and 5 in membrane microdomains called lipid rafts. We performed a series of analyses, either by biochemical methods or fluorescence resonance energy transfer (FRET) technique, on normal cells (i.e. lymphocytes, fibroblasts, endothelial cells), on a panel of human cancer B-cell lines as well as on CD19+ lymphocytes from patients with B-chronic lymphocytic leukemia, treated with different TRAIL ligands, that is, recombinant soluble TRAIL, specific agonistic antibodies to DR4 and DR5, or CD34+ TRAIL-armed cells. Irrespective to the expression levels of DRs, a molecular interaction between ganglioside GM3, abundant in lymphoid cells, and DR4 was detected. This association was negligible in all non-transformed cells and was strictly related to TRAIL susceptibility of cancer cells. Interestingly, lipid raft disruptor methyl-beta-cyclodextrin abrogated this susceptibility, whereas the chemotherapic drug perifosine, which induced the recruitment of TRAIL into lipid microdomains, improved TRAIL-induced apoptosis. Accordingly, in ex vivo samples from patients with B-chronic lymphocytic leukemia, the constitutive embedding of DR4 in lipid microdomains was associated per se with cell death susceptibility, whereas its exclusion was associated with TRAIL resistance. These results provide a key mechanism for TRAIL sensitivity in B-cell malignances: the association, within lipid microdomains, of DR4 but not DR5, with a specific ganglioside, that is the monosialoganglioside GM3. On these bases we suggest that lipid microdomains could exert a catalytic role for DR4-mediated cell death and that an ex vivo quantitative FRET analysis could be predictive of cancer cell sensitivity to TRAIL.
机译：肿瘤坏死因子相关的凋亡诱导配体（TRAIL）充当癌细胞的凋亡诱导剂，而保留非肿瘤细胞靶标。但是，一些I / II期临床试验表明该分子的益处有限。在目前的工作中，我们调查了细胞对TRAIL连接的敏感性是否可能是由于在称为脂质筏的膜微区中存在TRAIL死亡受体（DRs）4和5所致。我们通过生化方法或荧光共振能量转移（FRET）技术，对一组正常的细胞（即淋巴细胞，成纤维细胞，内皮细胞），人类癌症B细胞系以及CD19 <来自B型慢性淋巴细胞性白血病患者的sup> + 淋巴细胞，用不同的TRAIL配体（即重组可溶性TRAIL，针对DR4和DR5的特异性激动抗体或CD34 + TRAIL-武装部队。不论DRs的表达水平如何，都检测到在淋巴样细胞中丰富的神经节苷脂GM3与DR4之间的分子相互作用。这种联系在所有未转化的细胞中都是微不足道的，并且与癌细胞对TRAIL的敏感性密切相关。有趣的是，脂质筏破坏剂甲基-β-环糊精消除了这种敏感性，而诱导TRAIL募集到脂质微区中的化疗药物perifosine改善了TRAIL诱导的细胞凋亡。因此，在来自B慢性淋巴细胞性白血病患者的离体样品中，DR4在脂质微区的组成性嵌入本身与细胞死亡易感性有关，而其排斥与TRAIL抗性有关。这些结果为TRAIL在B细胞恶性肿瘤中的敏感性提供了关键机制：在脂质微结构域内，DR4而非DR5与特定神经节苷脂即单唾液酸神经节苷脂GM3相关联。在这些基础上，我们建议脂质微区可能在DR4介导的细胞死亡中发挥催化作用，而离体定量FRET分析可以预测癌细胞对TRAIL的敏感性。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

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