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MECHNISM OF APOPTOSIS INDUCED BY MEMBRANE LIPID SYGNALING

膜脂信号诱导细胞凋亡的机制

基本信息

批准号：
12470042
负责人：
NOZAWA Yoshinori
金额：
$ 7.94万
依托单位：
INSTITUTE OF APPLIED BIOCHEMISTRY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470042/
关键词：
APOPTOSIS SPHINGOMYELIN CERAMIDE PHOSPHOLIPASE D AKT PHOSPHATIDYLINOSITOL 3-KINASE スフィンゴミエリン代謝

项目摘要

Abundant studies have provided substantial evidence to indicate that sphingolipid metabolism, ceramide, plays a key role in induction of apoptosis. The anti-cancer drug, camptothecine (CPT) induced genotoxic apoptosis in human prostate cancer LNCaP cells. During the apoptosis intracellular ceramide level was elevated time-dependently after CPT-treatment. No changes were observed in activities of both neutral and acid SMases. The pretreatment with the inhibitor of ceramide synthesis, fumonisin Bi, almost completely abrogated marked ceramide accumulation. These results suggest evidence that ceramide is produced via de novo pathway but not via sphingomyelin hydrolysis pathway. Furthermore, it was to be noted that the same treatment with fumonisin Bi did not affect DNA fragmentation as assessed by ladder formation, thereby leading us to propose that ceramide accumulation may be independent of apoptosis in this system. Sphingosine 1-phosphate (SiP) is known to act as antiapoptosis. SiP stimulation of EDG3-overexpressing CHO cells induced activation of survival signaling enzymes, PLD, PT 3-kinase, and Akt. SiP-induced activation of PT 3-kinase and Akt was abrogated by 1-butanol, which inhibited SiP-induced accumulation of phosphatidic acid (PA) by PLD, suggesting that PLD participates in the activation of PT 3-kinase and Akt. Furthermore, it has been demonstrated that TNF-α induced sphingosine kinase (SPHK) activation in human hepatocytes, and dimethyisphingosine, a SPHK inhibitor, inhibited PI3K/Akt pathway and potentiated TNF-α-mediated hepatocyte apoptosis. These results suggest that SPHK and SiP play a role in cell survival through activation of PI3K/Akt signaling pathway.

大量的研究已经提供了大量的证据表明，鞘脂代谢，神经酰胺，在诱导细胞凋亡中起着关键作用。抗癌药物喜树碱（CPT）可诱导人前列腺癌LNCaP细胞发生遗传毒性凋亡。在凋亡过程中，CPT处理后细胞内神经酰胺水平呈时间依赖性升高。中性和酸性SMases的活性没有观察到变化。预处理与神经酰胺合成的抑制剂，伏马菌素铋，几乎完全废除了显着的神经酰胺积累。这些结果表明，神经酰胺是通过从头途径，而不是通过鞘磷脂水解途径产生的证据。此外，值得注意的是，通过梯状形成评估，伏马菌素Bi的相同处理并不影响DNA片段化，从而使我们提出神经酰胺积累可能与该系统中的细胞凋亡无关。已知鞘氨醇1-磷酸（SiP）具有抗凋亡作用。EDG 3过表达CHO细胞的SiP刺激诱导存活信号传导酶PLD、PT 3-激酶和Akt的活化。1-丁醇可抑制SiP诱导的PT 3-kinase和Akt的激活，而PLD可抑制SiP诱导的磷脂酸（phosphatidic acid，PA）的积累，提示PLD参与了PT 3-kinase和Akt的激活。TNF-α可诱导人肝细胞鞘氨醇激酶（SPHK）活化，SPHK抑制剂二甲基鞘氨醇可抑制PI 3 K/Akt通路，增强TNF-α介导的肝细胞凋亡。这些结果表明SPHK和SiP通过激活PI 3 K/Akt信号通路在细胞存活中起作用。