Arachidonic acid metabolism via cytosolic phospholipase A2alpha induces cytotoxicity in niemann-pick disease type C cells.
Arachidonic acid metabolism via cytosolic phospholipase A2alpha induces cytotoxicity in niemann-pick disease type C cells.
复制标题
花生四烯酸通过胞质磷脂酶 A2α 代谢可诱导尼曼皮克病 C 型细胞的细胞毒性。
DOI：
10.1002/jcp.23025
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发表时间：
2012
期刊：
影响因子：
5.6
通讯作者：
Nakamura H. et al.
中科院分区：
文献类型：
--
作者：
山口 賀章;岡村 均;松下 英明;Nakamura H. et al.
C型尼曼-匹克病（NPC）是由NPC 1或NPC 2基因突变引起的神经退行性脂质沉积症。任一蛋白质的功能丧失导致胆固醇和其他脂质的内体积累。在这里，我们报告说，与野生型细胞相比，NPC 1缺陷型中国仓鼠卵巢细胞表现出花生四烯酸（AA）的释放和前列腺素E2的合成增加。用胞浆磷脂酶A2α（cPLA 2 α）选择性抑制剂处理和在脂蛋白缺乏培养基中培养均可抑制AA的释放增强。NPC细胞和野生型细胞之间环氧合酶-1和-2的表达没有差异。U18666 A，一种常用于模拟NPC的胆固醇转运抑制剂，也增加了L929小鼠纤维肉瘤细胞中AA的释放。此外，U18666 A诱导的活性氧（ROS）的形成导致L929细胞中细胞死亡和细胞周期延迟/停滞的诱导。有趣的是，U18666 A诱导的这些反应在cPLA 2 α敲低的L929细胞中弱得多。这些结果表明cPLA 2 α-AA通路在NPC细胞的细胞毒性和ROS形成中起重要作用。J.细胞。227：2847-2855，2012。© 2011 Wiley Periodicals，Inc.
Niemann–Pick disease type C (NPC) is a neurodegenerative lipid storage disorder caused by mutations in NPC1 or NPC2 genes. Loss of function of either protein results in the endosomal accumulation of cholesterol and other lipids. Here, we report that NPC1‐deficient Chinese hamster ovary cells exhibit increased release of arachidonic acid (AA) and synthesis of prostaglandin E2compared with wild‐type cells. The enhanced release of AA was inhibited by both treatment with the selective inhibitor of cytosolic phospholipase A2α (cPLA2α) and cultivation in lipoprotein‐deficient medium. There was no difference in the expression of both cyclooxygenase‐1 and ‐2 between NPC cells and wild‐type cells. U18666A, a cholesterol transport‐inhibiting agent commonly used to mimic NPC, also increased the release of AA in L929 mouse fibrosarcoma cells. Furthermore, U18666A‐induced formation of reactive oxygen species (ROS) resulted in the induction of cell death and cell cycle delay/arrest in L929 cells. Interestingly, these responses induced by U18666A were much weaker in cPLA2α knockdown L929 cells. These results suggest that cPLA2α‐AA pathway plays important roles in the cytotoxicity and the ROS formation in NPC cells. J. Cell. Physiol. 227: 2847–2855, 2012. © 2011 Wiley Periodicals, Inc.