beta-连环素与GRP78相互作用调控大肠癌细胞能量代谢的分子机制研究

项目名称： beta-连环素与GRP78相互作用调控大肠癌细胞能量代谢的分子机制研究

项目编号： No.31271516

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 李卓玉

作者单位： 山西大学

项目金额： 85万元

中文摘要： 葡萄糖和谷氨酰胺代谢重塑是肿瘤细胞的重要特征之一。beta-连环素是Wnt信号通路中的关键成员，在多种肿瘤尤其是肠癌腺瘤的形成中起重要作用。葡萄糖调节蛋白78（GRP78）是位于内质网中的重要分子伴侣，在多种人类肿瘤组织中高表达。本课题前期研究表明，葡萄糖饥饿条件下大肠癌细胞中GRP78和谷氨酰胺代谢调控因子c-Myc蛋白呈明显高表达，且发现GRP78与beta-连环素、葡萄糖转运蛋白-1（Glut-1）有相互作用，这些相互作用可能促进了beta-连环素细胞核转位并激活c-Myc的表达，以加快谷氨酰胺代谢来补偿葡萄糖缺乏。本课题将研究葡萄糖饥饿诱导下，c-Myc在谷氨酰胺代谢和细胞存活中的作用；GRP78与beta-连环素相互作用促进c-Myc表达的分子机制；GRP78变化对Glut-1表达和细胞膜转位的影响。以新的视角阐明葡萄糖和谷氨酰胺代谢之间的关系，为肿瘤治疗提供新的思路和靶点。

中文关键词： 葡萄糖调节蛋白78；β-连环素；糖酵解；谷氨酰胺代谢；三羧酸循环

英文摘要： Remodeling of glucose and glutamine metabolism is one of the important characteristics of tumor cells. β-catenin (β-cat), which is a crucial protein of Wnt signal pathway, plays important roles in the formation of several types of tumors, especially in colorectal cancer adenoma. Glucose regulated protein 78 (GRP78) is referred as an important chaperone located in the endoplasmic reticulum. It is highly expressed in a few human cancers. Our previous study indicated that the expression of GRP78 and c-Myc were significantly elaveted in colorectal cancer cells under the glucose-deprived conditions. We further identified the interactions of GRP78 with β-catenin and glucose transporter 1 (Glut-1). Those interactions may promote the nuclear translocation of β-catenin and subsequent activation of c-Myc expression. We speculate that glucose deprivation-induced c-Myc is likely to accelerate the glutamine metabolism and play a compensatory effect on glucose metabolism. In this project, we intend to identify the role of the induced c-Myc protein in glutamine metabolism under the glucose-starved conditions. The molecular mechanism of GRP78-β-catenin and β-catenin-c-Myc promoter interactions will be studied in detail. Furthermore, the regulation of GRP78 on Glut-1 expression and its membrane translocation will be investigated

英文关键词： GRP78；β-catenin；Glycolysis；Glutamine metabolism；TCA