PGAM1在mTOR诱导肿瘤糖酵解中的作用

Aberrant metabolism is one of the hallmarks of cancer cells. In 1920s, Otto Warburg discovered that unlike in normal cells, tumor cells preferentially metabolize glucose by glycolysis, even in the presence of oxygen; this process was also called "Warburg effect". However, key questions about why and how cancer cells perform this highly glycolytic phenotype is still not well understood. The RTKs-PI3K/AKT-mTOR signaling pathway is a sensor in cells that regulates the execution of cell survival in response to growth factors, nutrients, stress and energy, it is also one of the most frequently altered pathways in cancer cells. Our published work discovered that hyperactivation of mTOR signaling pathway promotes the Warburg effect; moreover, we found that the expression of PGAM1 was significantly increased in mTOR hyperactivated cells. PGAM1 is one of the important enzymes in the glycolytic pathway, and many studies suggested that it may participate in the aerobic glycolysis and tumorigenesis. Thus, we hypothesize that hyper- activation of mTOR pathway enhances the Warburg effect through up-regulation of PGAM1, which may play critical roles in tumor metabolism and development. Knockdown of PGAM1 can block the glycolysis, then reduce the tumor growth. We will investigate the role of PGAM1 in mTOR-mediated tumor glycolysis using gene knockout cell lines, gene over-expression and knockdown cell lines, as well as human tumor tissues. This project will help us to better understand the mechanism of tumor development, thus may provide novel targets for the treatment of aberrant mTOR-mediated tumor.

代谢异常是肿瘤的特征之一。Otto Warburg发现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的"Warburg效应"，但其发生机制、调控方式等至今仍未阐明。信号通路转导异常在肿瘤中尤为常见，其中RTK-PI3K/AKT-mTOR通路在控制细胞生长、增殖和能量代谢等过程中起重要作用。我们发表的前期工作表明，mTOR过度活化能够导致Warburg效应发生；此外，我们发现在mTOR高度活化的细胞中，PGAM1表达明显升高。PGAM1是糖酵解途径中重要的酶之一，研究表明其可能在糖代谢和肿瘤发生中发挥作用。我们假设：mTOR通过上调PGAM1诱导Warburg效应发生，进而导致肿瘤发生。抑制PGAM1可能阻断肿瘤糖代谢，控制肿瘤发展。我们将利用多种细胞模型和人肿瘤组织探讨PGAM1在mTOR诱导肿瘤糖酵解中的作用。本研究的实施有助于进一步认识肿瘤发生机制，为肿瘤靶向治疗提供新的方向。

Warburg效应（有氧糖酵解）是肿瘤的特征之一，该现象是指肿瘤细胞无论氧气充足与否，均选择进行产能效率较低的糖酵解途径，葡萄糖消耗、糖酵解速率以及乳酸生成均较正常细胞明显增加。然而，肿瘤细胞为什么会发生糖酵解，其在肿瘤发生中的作用及机制等，仍有待于进一步研究。.哺乳动物雷帕霉素靶蛋白(Mammalian target of rapamycin，mTOR)通路活化是肿瘤中最常见的信号通路异常。该通路中的抑癌基因如TSC1/2和PTEN的失活均可以导致mTOR通路过度活化，从而肿瘤的发生。我们的前期研究表明，mTOR通路活化能够促进Warburg效应的发生。在糖酵解途径中，磷酸甘油酸变位酶-1（Phosphoglycerate mutase 1，PGAM1）是重要的催化酶之一，在多种肿瘤组织中有高表达，且与糖代谢调节有关。然而，其在肿瘤中的作用及调节机制并不是很清楚。本研究我们探讨了糖酵解中的磷酸甘油酸变位酶-1（PGAM1）在mTOR通路活化导致的有氧糖酵解和肿瘤发生发展中的作用，并在人肺癌样本中验证了这一调节作用。.我们的研究结果表明在Tsc2-/-和Pten-/-的MEF中，PGAM1表达及活性均较野生型升高，且这种高表达及高活性可以被雷帕霉素抑制。人肿瘤细胞系加入雷帕霉素也可以看到PGAM1表达明显下降。此外，HIF1α稳定敲低的mTOR通路活化细胞中PGAM1表达下调，说明mTOR通路通过HIF1α来调控PGAM1表达；染色质免疫共沉淀证明HIF1α通过与启动子区的直接结合调控PGAM1表达。敲低PGAM1可下调糖酵解水平，细胞增殖和克隆形成，并减缓小鼠肿瘤生长。在NSCLC中，PGAM1是患者OS和PFS的独立预后影响因素，对指导患者预后判断具有重要意义。且PGAM1表达与pS6具有相关性，说明mTOR对PGAM1的调节也存在于肺癌组织中，mTOR通路可能通过调节PGAM1的表达发挥生物学作用。我们的研究结果表明，PGAM1是mTOR信号通路的主要下游效应分子之一，对mTOR通路活化诱导的Warburg效应及肿瘤发生起促进作用。PGAM1可能是肿瘤预后的标志物和肿瘤治疗的新靶点。