Lysosomal ceramide mediates gemcitabine-induced death of glioma cells
Lysosomal ceramide mediates gemcitabine-induced death of glioma cells
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DOI：
10.1007/s00109-009-0514-8
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发表时间：
2009-11-01
影响因子：
4.7
通讯作者：
Gulbins, Erich
中科院分区：
文献类型：
--
作者：
Dumitru, Claudia A.;Sandalcioglu, Ibrahim E.;Gulbins, Erich
许多研究表明，酸性鞘磷脂酶诱导的神经酰胺释放可诱导细胞凋亡。然而，酸性鞘磷脂酶/神经酰胺介导的死亡信号的机制与化疗药物治疗后至今尚未完全阐明。本研究表明，治疗胶质瘤细胞与临床可达到的剂量吉西他滨的结果在酸性鞘磷脂酶激活，神经酰胺的溶酶体积累，组织蛋白酶D激活，Bax插入线粒体，和细胞死亡。酸性鞘磷脂酶的药理学抑制或遗传缺陷阻止了这些事件，而酶的过度表达使细胞对吉西他滨敏感。同样，溶酶体功能的抑制剂也防止吉西他滨诱导的细胞死亡。我们的数据表明，吉西他滨诱导的信号转导的酸性鞘磷脂酶/神经酰胺系统的关键作用，并表明，溶酶体神经酰胺积累介导的化疗药物诱导的细胞死亡。
Acid sphingomyelinase-induced ceramide release has been shown by many studies to induce apoptosis in response to various stimuli. However, the mechanisms of acid sphingomyelinase/ceramide-mediated death signaling following treatment with chemotherapeutic drugs have not been fully elucidated thus far. The present study demonstrates that treatment of glioma cells with clinically achievable doses of gemcitabine results in acid sphingomyelinase activation, lysosomal accumulation of ceramide, cathepsin D activation, Bax insertion into the mitochondria, and cell death. Pharmacological inhibition or genetic deficiency of acid sphingomyelinase prevented these events while overexpression of the enzyme sensitized cells to gemcitabine. Likewise, inhibitors of lysosomal functions also prevent gemcitabine-induced cell death. Our data indicate a critical role of the acid sphingomyelinase/ceramide system for gemcitabine-induced signaling and suggest that lysosomal ceramide accumulation mediates cell death induced by a chemotherapeutic drug.