Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells
Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells
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DOI：
10.1158/0008-5472.can-03-3084
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发表时间：
2004-06-15
期刊：
影响因子：
11.2
通讯作者：
Kondo, S
中科院分区：
文献类型：
--
作者：
Daido, S;Kanzawa, T;Kondo, S
鞘脂神经酰胺已被认为是重要的第二信使，参与调节多种信号通路，尤其是细胞凋亡。然而，人们对神经酰胺诱导非凋亡细胞死亡的分子机制知之甚少。在本研究中，我们首先证明神经酰胺可诱导恶性胶质瘤细胞的非凋亡性细胞死亡。细胞死亡伴随着自噬的几个具体特征：细胞质中存在大量自噬空泡、酸性囊泡细胞器的发育、微管相关蛋白轻链3（LC3）的自噬体膜关联以及两种形式的LC3蛋白（LC3-I和LC3-II）的表达水平显着增加。我们还证明神经酰胺降低线粒体膜电位并激活死亡诱导线粒体蛋白 BNIP3 的转录，导致恶性胶质瘤细胞中其 mRNA 和蛋白的表达水平增加。此外，转染BNIP3基因的肿瘤细胞在没有神经酰胺的情况下会发生自噬。这些结果表明神经酰胺通过激活 BNIP3 诱导恶性神经胶质瘤细胞自噬性细胞死亡。这项研究增加了一个新概念来表征神经酰胺诱导恶性神经胶质瘤非凋亡性自噬细胞死亡的途径。
The sphingolipid ceramide has been recognized as an important second messenger implicated in regulating diverse signaling pathways especially for apoptosis. Very little is known, however, about the molecular mechanisms underlying nonapoptotic cell death induced by ceramide. In the present study, we first demonstrate that ceramide induces nonapoptotic cell death in malignant glioma cells. The cell death was accompanied by several specific features characteristic of autophagy: presence of numerous autophagic vacuoles in the cytoplasm, development of the acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3), and a marked increase in expression levels of two forms of LC3 protein (LC3-I and LC3-II). We additionally demonstrate that ceramide decreases mitochondrial membrane potential and activates the transcription of death-inducing mitochondrial protein, BNIP3, resulting in increased expression levels of its mRNA and protein in malignant glioma cells. Moreover, tumor cells transfected with BNIP3 gene undergo autophagy in the absence of ceramide. These results suggest that ceramide induces autophagic cell death in malignant glioma cells via activation of BNIP3. This study adds a new concept to characterize the pathways by which ceramide acts to induce nonapoptotic autophagic cell death in malignant gliomas.