细胞ATP生成异常- - Warburg效应的机理研究

项目名称： 细胞ATP生成异常- - Warburg效应的机理研究

项目编号： No.31271524

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： 方敏

作者单位： 北京大学

项目金额： 85万元

中文摘要： 细胞在癌变过程中发生了系统性的代谢重构（Metabolic reprogramming）,尤其表现在糖酵解途径的特异性强化（即Warburg效应），其机制远未阐明。申请人在前期工作中发现内质网UDP水解酶ENTPD5参与细胞糖酵解途径的调控，ENTPD5水平在前列腺癌细胞系（LNCaP）和前列腺肿瘤病例中显著升高。下调ENTPD5表达水平后，LNCaP细胞增殖能力降低、细胞膜表面多种生长因子受体减少、裸鼠移植瘤变小。这说明以ENTPD5为代表的细胞糖酵解途径的调节蛋白，可能作为治疗癌症的新靶点。基于申请人前期的工作基础，为解决有关Warburg效应的关键科学问题，本立项拟首先在体外重建糖酵解途径的无细胞体系，然后纯化和分离癌细胞中能够导致Warburg效应的关键调节因子，再通过裸鼠移植瘤模型验证这些因子在肿瘤发生中的作用，为进一步寻找新的化疗靶点和药物筛选提供理论支持。

中文关键词： 糖酵解；Warburg效应；信号转导；多聚泛素化；细胞凋亡

英文摘要： It has been well established that metabolic reprogramming coincides with every stage of cancer development ranging from initiation,through promotion, all the way to metastatic progression. Among all of the metabolically adaptive events sequentially emerged during cancer development, the enhancement of glycolysis even in the presence of ample oxygen, which is also defined as Warburg effect, is the longest standing enigma and most controversial issue in the history of cancer biology. Even today, the detail mechanism of Warburg effect still remains largely elusive. In our previous published paper (Fang M.,et al.,Cell, 143:711), ENTPD5, an endoplasmic reticulum UDP hydrolase has been demonstrated to be involved in the continuous upregulation of glycolysis, which is further recapitulated by the much higher expression level of ENTPD5 in human prostate cancer cell line LNCaP，PTEN knock-out MEF cells as well as tumour samples from human prostate cancer patients. Further more, the decrease of cell proliferating rate and the level of multiple cell growth factor receptors in LNCaP cells as well as the shrinkage of LNCaP xenografts in nude mice were achieved by specifically knocking-down of endogenous ENTPD5. The distinctive role of ENTPD5 in cancer development and Warburg effect underlines the fact that glycolytic regulato

英文关键词： Glycolysis；Warburg effect；Signal transduction；Poly-ubiquitination；apoptosis