Downregulation of ceramide synthase-6 during epithelial-to-mesenchymal transition reduces plasma membrane fluidity and cancer cell motility
Downregulation of ceramide synthase-6 during epithelial-to-mesenchymal transition reduces plasma membrane fluidity and cancer cell motility
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DOI：
10.1038/onc.2014.55
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发表时间：
2015-02-19
期刊：
影响因子：
8
通讯作者：
Legembre, P.
中科院分区：
文献类型：
--
作者：
Edmond, V.;Dufour, F.;Legembre, P.
上皮-间质转化（EMT）促进细胞运动，这对于恶性细胞的转移是重要的，并且阻断由免疫细胞和化疗方案触发的CD 95介导的凋亡信号传导。CD 95的同源配体CD 95 L可以被金属蛋白酶切割并作为可溶性分子（cl-CD 95 L）释放。与跨膜CD 95 L不同，cl-CD 95 L不诱导细胞凋亡，但触发细胞运动。使用电子顺磁共振显示EMT和cl-CD 95 L处理均导致有助于诱导细胞迁移的质膜流动性增加。除其他因素外，质膜的压实由膜中某些脂质如鞘脂的比例调节。对NCI肿瘤细胞系基因表达的综合分析显示，神经酰胺合成酶-6（CerS 6）的表达在EMT期间降低。此外，药理学和遗传学方法确定，癌细胞中CerS 6表达/活性的调节改变了C16-神经酰胺的水平，这反过来又影响质膜流动性和细胞运动性。因此，本研究确定CerS 6是一种新型EMT调节基因，在细胞迁移调节中具有关键作用。
Epithelial-to-mesenchymal transition (EMT) promotes cell motility, which is important for the metastasis of malignant cells, and blocks CD95-mediated apoptotic signaling triggered by immune cells and chemotherapeutic regimens. CD95L, the cognate ligand of CD95, can be cleaved by metalloproteases and released as a soluble molecule (cl-CD95L). Unlike transmembrane CD95L, cl-CD95L does not induce apoptosis but triggers cell motility. Electron paramagnetic resonance was used to show that EMT and cl-CD95L treatment both led to augmentation of plasma membrane fluidity that was instrumental in inducing cell migration. Compaction of the plasma membrane is modulated, among other factors, by the ratio of certain lipids such as sphingolipids in the membrane. An integrative analysis of gene expression in NCI tumor cell lines revealed that expression of ceramide synthase-6 (CerS6) decreased during EMT. Furthermore, pharmacological and genetic approaches established that modulation of CerS6 expression/activity in cancer cells altered the level of C16-ceramide, which in turn influenced plasma membrane fluidity and cell motility. Therefore, this study identifies CerS6 as a novel EMT-regulated gene that has a pivotal role in the regulation of cell migration.