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鞘氨醇激酶在抗抑郁药诱导胶质瘤细胞凋亡中的作用

批准号30672442 学科分类材料的设计与制备 ( E030701 )
项目负责人江大志 负责人职称 依托单位上海交通大学
资助金额0.00
万元
项目类别面上项目 研究期限2007 年 01 月 01 日 至
2009 年 12 月 31 日
中文主题词抗抑郁药:细胞凋亡:C6细胞:鞘氨醇激酶:CHOP
英文主题词antidepressant:apoptosis:C6 cell:sphingosine kinase:CHOP

摘要

中文摘要 肿瘤患者为抑郁症高发人群,抗抑郁药可改善肿瘤患者的情绪,且对多种慢性疼痛疗效确切,已成为肿瘤综合治疗的重要辅助手段。抗抑郁药对多种肿瘤细胞具直接的细胞毒作用,与其凋亡诱导作用有关,但机制不明。神经酰胺作为抑制细胞增殖的第二信使,可诱导细胞凋亡,鞘氨醇激酶通过降低神经酰胺的水平抑制细胞凋亡。抗抑郁药地昔帕明为鞘磷脂酶抑制剂,鞘磷脂酶水解底物鞘磷脂,可提高神经酰胺的含量。本课题研究地昔帕明对脑胶质瘤C6细胞鞘氨醇激酶表达的影响及其对细胞凋亡的调节作用,旨在阐明抗抑郁药诱导肿瘤细胞凋亡的分子机制,为抗抑郁药辅助肿瘤治疗提供新的理论依据和实验解释。本研究发现地昔帕明可提高C6细胞鞘氨醇激酶的表达水平。地昔帕明诱导凋亡的同时,可时间及剂量依赖性提高CHOP的表达水平,而对与受体介导的凋亡途径有关的Caspase8的活性以及线粒体膜电位均无影响,CHOP为内质网应激介导的凋亡途径的关键转录因子。抑制CHOP的表达可对抗地昔帕明的凋亡诱导作用。同时,地昔帕明能促进CHOP上游信号分子PERK及eIF的磷酸化并提高CHOP下游靶分子GADD34的表达,说明其凋亡诱导作用主要与内质网应激途径有关。
英文摘要 The incidence of depression is higher in cancer patient than in normal person. Antidepressant agent is the important auxiliary measure for treatment of depressive symptom among cancer patients. Also they are clinically prescribed to patients for the management of various chronic pains. Recent studies have provided considerable evidence that antidepressants possess a notable inhibitory effect on the proliferation of several malignant tumor cells in vitro which is related to their proapoptotic effects. But the apoptotic downstream signal pathway is still unclear and remains to be elucidated. The ceramide has been recognized as an important inhibitory second messager implicated in triggering apoptotic processes. Sphingosine kinase, being a key enzyme in modulating ceramide dynamic balance, serve as a crucial regulator of apoptosis. The tricyclic antidepressant desipramine causes a decrease in cellular acid sphingomyelinase. Acid sphingomyelinase is a lysosomal hydrolase that catalyzes the degradation of sphingomyelin to ceramide. The main purpose of our study is to observe the regulatory effect of antidepressant desipramine on the expression of sphingosine kinase and to determine the mechanism in desipramine-induced apoptosis in rat glioma C6 cells, so as to provide experimental basis for the comprehensive treatment of cancer patient. The expression of sphingosine kinase in C6 cells was increased after the treatment of desipramine. Desipramine treatment significantly elevated the mRNA and protein level of endoplasmic reticulum (ER) stress regulator –CEBP homology protein / growth arrest and DNA damage (CHOP) both in time and dose dependent manner, but without the concomitance of activation of caspase8 which is mainly responsible for receptor mediated apoptotic death route. In the mean time, the mitochondrial membrane potential of C6 cells remained unchanged. Moreover, the knockdown of CHOP with the CHOP-specific siRNA could decrease the cytotoxicity and proapototic action of desipramine in C6 cells. Simultaneously, it could increase the phosphorylation of PERK and eIF, and furthermore augmented the mRNA expression of its main targeting molecule GADD34. Accordingly, these results indicated that the CHOP-dependent ER stress pathway may be responsible for the desipramine-induced apoptosis in C6 glioma cells.
结题摘要 肿瘤患者为抑郁症高发人群,抗抑郁药可改善肿瘤患者的情绪,且对多种慢性疼痛疗效确切,已成为肿瘤综合治疗的重要辅助手段。抗抑郁药对多种肿瘤细胞具直接的细胞毒作用,与其凋亡诱导作用有关,但机制不明。神经酰胺作为抑制细胞增殖的第二信使,可诱导细胞凋亡,鞘氨醇激酶通过降低神经酰胺的水平抑制细胞凋亡。抗抑郁药地昔帕明为鞘磷脂酶抑制剂,鞘磷脂酶水解底物鞘磷脂,可提高神经酰胺的含量。本课题研究地昔帕明对脑胶质瘤C6细胞鞘氨醇激酶表达的影响及其对细胞凋亡的调节作用,旨在阐明抗抑郁药诱导肿瘤细胞凋亡的分子机制,为抗抑郁药辅助肿瘤治疗提供新的理论依据和实验解释。本研究发现地昔帕明可提高C6细胞鞘氨醇激酶的表达水平。地昔帕明诱导凋亡的同时,可时间及剂量依赖性提高CHOP的表达水平,而对与受体介导的凋亡途径有关的Caspase8的活性以及线粒体膜电位均无影响,CHOP为内质网应激介导的凋亡途径的关键转录因子。抑制CHOP的表达可对抗地昔帕明的凋亡诱导作用。同时,地昔帕明能促进CHOP上游信号分子PERK及eIF的磷酸化并提高CHOP下游靶分子GADD34的表达,说明其凋亡诱导作用主要与内质网应激途径有关。

成果

序号 标题 类型 作者
1 Allostatic tumor-burden induces depression-associated changes in hepatoma-bearing mice 期刊 祁红|
2 Dichloroacetate shifts the metabolism from glycolysis to glucose oxidation and exhibits synergistic growth inhibition with cisplatin in HeLa cells. 期刊 祁红|
3 Synthesis and evaluation of k-opioid receptor agonistic activity and antinociceptive effect of novel morphine analogues, 7a -phenyl -6a , 14a -endo-etheno-tetrahydrothebaine with substituted o-, m- an 期刊 祁红|
4 Is acupuncture beneficial in depression: A meta-analysis of 8 randomized controlled trials? 期刊 祁红|
5 抗抑郁药对抗奥沙利铂诱发的神经病理性疼痛的作用研究 期刊 祁红|

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