神经酰胺调控Ca2+-ERS通路诱导涎腺腺样囊性癌细胞凋亡及其分子机制研究

项目名称： 神经酰胺调控Ca2+-ERS通路诱导涎腺腺样囊性癌细胞凋亡及其分子机制研究

项目编号： No.81472532

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李龙江

作者单位： 四川大学

项目金额： 75万元

中文摘要： 内质网功能在肿瘤细胞快速增殖和恶性物质分泌过程中起关键作用，持续强烈的外界刺激可干扰内质网功能，启动内质网应激(ERS)，激活下游广泛的促凋亡途径。靶向干预内质网并启动多重放大的凋亡信号，代表着肿瘤治疗的新策略。内质网Ca2+信号与ERS可协同诱导凋亡，然而其在肿瘤细胞中的级联串话机制不明。申请者前期研究发现神经酰胺可激活涎腺腺样囊性癌细胞的ERS反应，并促进内质网Ca2+释放。本课题拟在此基础上采用基因突变小鼠模型和荷瘤裸鼠模型，检测神经酰胺对正常涎腺组织和肿瘤组织的生物学效应；通过慢病毒转染对细胞信号通路各级分子采用增效或失效设计，研究通过内质网Ca2+信号介导，神经酰胺调控的ERS促凋亡途径与Ca2+释放凋亡途径级联串话，进而诱导细胞凋亡的分子机制。研究结果将在亚细胞器内质网水平上揭示神经酰胺诱导凋亡作用的分子机制，为开发新的肿瘤治疗方法提供理论和实验基础。

中文关键词： C01_口腔肿瘤；神经酰胺；内质网应激；信号通路；涎腺腺样囊性癌

英文摘要： The function of endoplasmic reticulum (ER) is the key to rapid proliferation of tumor cells and delivery of malignant substances. Strong external stimuli interrupt the function of endoplasmic reticulum, triggering the endoplasmic reticulum stress (ERS), and activating vast cascades of pro-apoptosis signaling pathways. It represents a new anti-tumor therapeutic strategy to target the ER and to trigger downstream pro-apoptosis signaling cascades. The Ca2+ signal in the ER synergize with ERS to promote apoptosis, but little is known about the mechanism of cross-talk between the two signaling pathways in the tumor cells. We had discovered in our previous study that ceramide could initiate ERS in the salivary adenoid cystic carcinoma cell lines, and that ceramide enhanced the Ca2+ release from the ER. Basing on our discovery, we planned in this project to adopt mouse model with genetic point mutation, and to establish tumor-bearing mouse model. Biological effects of ceramide on salivary gland tissue and tumor tissue were examined. Lentiviral transfection was performed to up-regulate or down-regulate cell signaling molecule in the cascades investigated, thus to explore the molecular mechanism of ceramide-midiated regulation of salivary adenoid cystic carcinoma cell apoptosis by crosstalk between Ca2+ signaling and ERS depended apoptotic pathways. Project results will disclose the molecular mechanism of ceramide-induced apoptotic effects on endoplasmic reticulum level, thus laying theoretical and experimental foundation for new anti-tumor therapies.

英文关键词： C01_oral cancer;Ceramide;endoplasmic reticulum stress;signaling pathway;salivary adenoid cystic carcinoma