AMPK调控PKM2的功能及分子机制研究

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” This phenomenon is one of features of tumor cells different from normal cells. Pyruvate kinase M2 (PKM2) is a key enzyme of the glycolytic pathway, catalyzing conversion of phosphoenolpyruvate to pyruvate. PKM2 is an important regulator of the Warburg effect, however, the underlying mechanism is not clear. Our preliminary results showed that AMPK, the cellular energy sensor, directly phosphorylates PKM2 and regulates the Warburg effect. This study will focus on AMPK-PKM2 cascade, investigate the function and underlying molecular mechanisms of AMPK-PKM2 signaling pathway in tumorigenesis and cell metabolism. Our study will not only prove new insight for the cancer cell metabolic network, but also provide new strategies for cancer diagnosis and treatment.

肿瘤细胞无论氧气存在与否都主要依赖糖酵解方式进行代谢，消耗大量葡萄糖并伴有乳酸的产生，这一现象称为有氧糖酵解，即Warburg效应，是肿瘤细胞区别于正常细胞的特征之一。丙酮酸激酶M2(PKM2)是糖酵解途径最后一步的关键酶，是Warburg效应的重要调控因子，然而其发生作用的分子机制和调控并不十分清楚。我们前期研究发现，细胞能量感受器AMPK能直接磷酸化PKM2并调控Waruburg效应。本项目以AMPK-PKM2为研究对象，围绕“肿瘤细胞代谢与癌症发生的关系”这一关键科学问题，综合运用生物化学、细胞生物学、蛋白质组学、遗传学等学科的理论和技术，在分子、细胞、动物整体水平，多角度多层面系统地研究其在肿瘤发生发展中的重要作用和分子机制。本项目不仅能够阐明AMPK-PKM2信号通路在肿瘤发生发展中的分子机理，补充和完善现有的癌细胞代谢理论体系，而且能为肿瘤的防诊治提供新的思路和靶点。

肿瘤细胞主要利用有氧糖酵解（也称Warburg效应）方式作为主要的代谢途径。丙酮酸激酶M2剪接体亚型（PKM2）通常在多种类型肿瘤中上调，在Warburg效应和肿瘤发生中起重要的调控作用。PKM2在Warburg效应中的作用已经比较明确，但其代谢调控机制仍不清楚。本项目研究表明能量感应器AMPK激酶直接结合PKM2并将PKM2磷酸化，该磷酸化促进了PKM2四聚体组装，影响了其在核内的累积以及其蛋白激酶活性，导致Warburg效应及肿瘤细胞生长受到抑制。本研究鉴定了一个新的依赖于AMPK磷酸化的PKM2功能调控分子机制， 对于理解LKB1-AMPK 与PKM2介导的肿瘤代谢之间的相互作用有重要的意义。以上研究结果还为针对AMPK、PKM激酶活性的肿瘤抑制性药物开发提供依据。