Ceramide launches an acute anti-adhesion pro-migration cell signaling program in response to chemotherapy.
Ceramide launches an acute anti-adhesion pro-migration cell signaling program in response to chemotherapy.
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DOI：
10.1096/fj.202000205r
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发表时间：
2020-06
期刊：
影响因子：
--
通讯作者：
Hannun YA
中科院分区：
文献类型：
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作者：
Canals D;Salamone S;Santacreu BJ;Nemeth E;Aguilar D;Hernandez-Corbacho MJ;Adada M;Staquicini DI;Arap W;Pasqualini R;Haley J;Obeid LM;Hannun YA
据报道，化疗可上调鞘磷脂酶并增加细胞神经酰胺，通常与诱导细胞死亡有关。在这项工作中，我们表明亚致死剂量的阿霉素和伏立诺他仍然增加细胞神经酰胺，这是主要位于质膜。为了探究这种特定的神经酰胺库的可能功能，我们使用重组酶来模拟化学疗法治疗后质膜上神经酰胺的生理水平。使用质谱和网络分析，然后通过实验证实，结果显示，这种神经酰胺库急性调节细胞粘附和细胞迁移途径，与通常建立的神经酰胺功能（例如细胞死亡）的连接较弱。中性鞘磷脂酶2（nSMase2）被确定为负责产生质膜神经酰胺化疗治疗后，和神经酰胺在质膜和nSMase2是必要的，足以介导化疗对细胞粘附和迁移的这些“副作用”。这是第一次询问神经酰胺的特定池的急性信号传导功能，结果定义质膜神经酰胺作为急性信号传导效应物，其对于在化疗应激下调节细胞粘附和细胞迁移是必要的和足够的。
Chemotherapy has been reported to upregulate sphingomylinases and increase cellular ceramide, often linked to the induction to cell death. In this work, we show that sublethal doses of doxorubicin and vorinostat still increased cellular ceramide, which was located predominantly at the plasma membrane. To interrogate possible functions of this specific pool of ceramide, we used recombinant enzymes to mimic physiological levels of ceramide at the plasma membrane upon chemotherapy treatment. Using mass spectrometry and network analysis, followed by experimental confirmation, the results revealed that this pool of ceramide acutely regulates cell adhesion and cell migration pathways with weak connections to commonly stablished ceramide functions (e.g. cell death). Neutral sphingomyelinase 2 (nSMase2) was identified as responsible for the generation of plasma membrane ceramide upon chemotherapy treatment, and both ceramide at the plasma membrane and nSMase2 were necessary and sufficient to mediate these “side” effects of chemotherapy on cell adhesion and migration. This is the first time a specific pool of ceramide is interrogated for acute signaling functions and the results define plasma membrane ceramide as an acute signaling effector necessary and sufficient for regulation of cell adhesion and cell migration under chemotherapeutical stress.
DOI：
10.1093/bioinformatics/btx419
发表时间：
2018-01-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Elliott A;Leicht E;Whitmore A;Reinert G;Reed-Tsochas F
通讯作者：
Reed-Tsochas F