...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Oncogene >Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma
【24h】

Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma

机译：细胞质Dynein调节鞘氨酸激酶2的亚细胞定位，以引发胶质母细胞瘤中的肿瘤抑制功能

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

摘要

While the two mammalian sphingosine kinases, SK1 and SK2, both catalyze the generation of pro-survival sphingosine 1-phosphate (S1P), their roles vary dependent on their different subcellular localization. SK1 is generally found in the cytoplasm or at the plasma membrane where it can promote cell proliferation and survival. SK2 can be present at the plasma membrane where it appears to have a similar function to SK1, but can also be localized to the nucleus, endoplasmic reticulum or mitochondria where it mediates cell death. Although SK2 has been implicated in cancer initiation and progression, the mechanisms regulating SK2 subcellular localization are undefined. Here, we report that SK2 interacts with the intermediate chain subunits of the retrograde-directed transport motor complex, cytoplasmic dynein 1 (DYNC1I1 and -2), and we show that this interaction, particularly with DYNC1I1, facilitates the transport of SK2 away from the plasma membrane. DYNC1I1 is dramatically downregulated in patient samples of glioblastoma (GBM), where lower expression of DYNC1I1 correlates with poorer patient survival. Notably, low DYNC1I1 expression in GBM cells coincided with more SK2 localized to the plasma membrane, where it has been recently implicated in oncogenesis. Re-expression of DYNC1I1 reduced plasma membrane-localized SK2 and extracellular S1P formation, and decreased GBM tumor growth and tumor-associated angiogenesis in vivo. Consistent with this, chemical inhibition of SK2 reduced the viability of patient-derived GBM cells in vitro and decreased GBM tumor growth in vivo. Thus, these findings demonstrate a tumor-suppressive function of DYNC1I1, and uncover new mechanistic insights into SK2 regulation which may have implications in targeting this enzyme as a therapeutic strategy in GBM.
机译：虽然两种哺乳动物鞘氨酸激酶，SK1和SK2，SK1和SK2均催化产生胰岛素的磷磷酸三磷酸钠（S1P），其作用变化依赖于其不同的亚细胞定位。 SK1通常在细胞质或血浆膜中发现，可以促进细胞增殖和存活。 SK2可以存在于血浆膜中，在那里它看起来具有与SK1类似的功能，但也可以局限于其中介导细胞死亡的细胞核，内质网或线粒体。虽然SK2已经涉及癌症启动和进展，但是调节SK2亚细胞定位的机制是未定义的。在这里，我们报告SK2与逆行定向的传输电机复合物，细胞质Dynein 1（Dync1i1和-2）的中间链亚基相互作用，并且我们表明这种相互作用，特别是与Dync1i1的相互作用有助于SK2的运输远离质膜。 Dync1i1在胶质母细胞瘤（GBM）的患者样品中显着下调，其中Dync1i1的较低表达与较差的患者存活率相关。值得注意的是，GBM细胞中的低DYNC1I1表达与局部化的更多SK2，最近涉及一种血管生成。 Dync1i1减少的血浆膜 - 局部SK2和细胞外S1P形成的再表达，并降低了体内GBM肿瘤生长和肿瘤相关血管生成。符合这一致的，SK2的化学抑制减少了体外患者衍生的GBM细胞的可行性并降低了体内GBM肿瘤生长。因此，这些研究结果表明Dync1i1的肿瘤抑制功能，并将新的机械洞察力揭示进入SK2调节，这可能对靶向该酶作为GBM中的治疗策略具有意义。

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