Ceramide promotes apoptosis in lung cancer-derived A549 cells by a mechanism involving c-Jun NH2-terminal kinase
Ceramide promotes apoptosis in lung cancer-derived A549 cells by a mechanism involving c-Jun NH2-terminal kinase
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DOI：
10.1158/0008-5472.can-04-1552
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发表时间：
2004-11-01
期刊：
影响因子：
11.2
通讯作者：
Ruvolo, PP
中科院分区：
文献类型：
--
作者：
Kurinna, SM;Tsao, CC;Ruvolo, PP
神经酰胺调节涉及细胞衰老、细胞周期和凋亡的多种信号通路。已知神经酰胺可有效激活许多应激调节酶，包括c-Jun NH 2-末端激酶（JNK）。虽然神经酰胺促进人肺癌A549细胞的凋亡，但JNK在此过程中的作用尚不清楚。在这里，我们报告，神经酰胺促进A549细胞凋亡的机制，涉及JNK。JNK抑制剂SP 600125被证明有效地保护细胞免受神经酰胺的致死作用。为了了解JNK介导的途径可能涉及，一些JNK靶蛋白进行了检查，包括转录因子，c-jun，和凋亡调节蛋白Bcl-X-L和Bim。A549细胞在核组分中表现出磷酸化c-jun的基础水平，表明这些细胞中存在活性c-Jun。发现神经酰胺抑制c-jun磷酸化，表明JNK介导的c-jun磷酸化不太可能参与神经酰胺诱导的细胞凋亡。神经酰胺不促进Bcl-X-L磷酸化。另一方面，神经酰胺促进Bim的磷酸化，并诱导活性JNK从细胞核易位到细胞质和线粒体组分。神经酰胺介导的JNK定位变化与观察到的c-Jun和Bim磷酸化状态变化一致。此外，神经酰胺促进Bim易位到线粒体。最近已显示Bim的线粒体定位促进细胞凋亡。这些结果表明，JNK可能参与神经酰胺诱导的A549细胞凋亡的机制，涉及Bim。
Ceramide regulates diverse signaling pathways involving cell senescence, the cell cycle, and apoptosis. Ceramide is known to potently activate a number of stress-regulated enzymes, including the c-Jun NH2-terminal kinase (JNK). Although ceramide promotes apoptosis in human lung cancer-derived A549 cells, a role for JNK in this process is unknown. Here, we report that ceramide promotes apoptosis in A549 cells by a mechanism involving JNK. The JNK inhibitor SP600125 proved effective at protecting cells from the lethal effects of ceramide. To understand which JNK-mediated pathway may be involved, a number of JNK target proteins were examined, including the transcription factor, c-jun, and the apoptotic regulatory proteins Bcl-X-L and Bim. A549 cells exhibited basal levels of phosphorylated c-jun in nuclear fractions, revealing that active c-Jun is present in these cells. Ceramide was found to inhibit c-jun phosphorylation, suggesting that JNK-mediated phosphorylation of c-jun is not likely involved in ceramide-induced apoptosis. Ceramide did not promote Bcl-X-L phosphorylation. On the other hand, ceramide promoted phosphorylation of Bim and induced translocation of active JNK from the nucleus to the cytoplasm and mitochondrial fraction. Ceramide-mediated changes in localization of JNK were consistent with the observed changes in phosphorylation status of c-Jun and Bim. Furthermore, ceramide promoted Bim translocation to the mitochondria. Mitochondrial localization of Bim has been shown recently to promote apoptosis. These results suggest that JNK may participate in ceramide-induced apoptosis in A549 cells by a mechanism involving Bim.