PKM2 coordinates glycolysis and glutaminolysis in cancer cells

描述(申请人提供)：已有文献证明致癌产物和生长信号会改变癌细胞的新陈代谢。然而，肿瘤细胞的新陈代谢调节是否以及如何反馈影响肿瘤的进展还知之甚少。肿瘤细胞如何协调糖酵解和谷氨酰胺分解这两条主要代谢途径之间的变化也不是很清楚。我们观察到PKM2定位于细胞核。核蛋白PKM2作为转录共激活子，激活基因转录。更重要的是，关键的糖酵解酶PKM2作为一种蛋白激酶，在Y705处磷酸化STAT3，从而激活基因转录。我们的实验证明，PKM2的蛋白激酶活性介导了PKM2促进细胞增殖的效应。此外，我们的研究还发现，PKM2上调了谷氨酰胺酶的表达，表明了癌细胞代谢和细胞增殖之间的反馈循环，以及这种糖酵解酶在协调糖酵解和谷氨酰胺分解的变化中的潜在功能。这项拟议的研究项目的目标是了解PKM2在肿瘤进展中的作用。我们提出了三个特定的目标来验证我们的假设，即糖酵解酶PKM2不仅通过调节有利于生物合成的糖酵解代谢产物流动，而且通过调节谷氨酰胺分解，促进细胞增殖和肿瘤进展。通过 PKM2作用于多种不同的代谢过程，在肿瘤进展过程中发挥协调代谢变化和细胞增殖的作用。这个项目中提出的实验将首先测试PKM2是否真的激活了谷氨酰胺分解。第二个特定目标中提出的实验将解决PKM2激活谷氨酰胺分解是否也在体内发生的问题。在具体目标3中，我们将阐明生长信号如何影响PKM2在谷氨酰胺分解激活中的作用。我们的研究最终将应用于 致力于癌症治疗新策略的开发。

DESCRIPTION (provided by applicant): It is well documented that oncogenic products and growth signals alter metabolism of cancer cells. However, it is less well understood whether and how the metabolism adjustments of tumor cells feedback to affect tumor progression. It is also not well understood how cancer cells coordinate the alterations between two major metabolism pathways, glycolysis and glutaminolysis. We observed that that PKM2 localized to the cell nucleus. The nuclear PKM2 functions as a transcription co-activator to activate the gene transcription. More importantly, PKM2, a key glycolysis enzyme, functions as a protein kinase to phosphorylate stat3 at Y705 therefore activating gene transcription. Our experiments demonstrate that the protein kinase activity of PKM2 mediates the effects of PKM2 in promoting cell proliferation. In addition, our study revealed that PKM2 upregulates glutaminase expression, indicating a feedback loop between cancer cell metabolism and cell proliferation, and potential function of this glycolysis enzyme in coordinating the changes of both glycolysis and glutaminolysis. The goal of this proposed research project is to understand the role of PKM2 in tumor progression. We propose three specific aims to test our hypothesis that PKM2, a glycolysis enzyme, facilitates cell proliferation and tumor progression not only by adjusting glycolytic metabolites flow in favor of biosynthesis, but also by regulating the glutaminolysis. By acting at multiple different metabolism processes, PKM2 fulfill the role of coordinating metabolism alterations and cell proliferation during tumor progression. The experiments proposed in this project will first test whether PKM2 indeed activates glutaminolysis. Experiments proposed in the 2nd specific aim will address whether activation of glutaminolysis by PKM2 also occurs in vivo. In the specific aim 3, we will elucidate how the growth signals affect the function of PKM2 in activation of glutaminolysis. Our studies will ultimately be applied to the development of new strategies for cancer treatment.