PKM2 coordinates glycolysis and glutaminolysis in cancer cells

描述（由申请人提供）：有充分的证据表明致癌产物和生长信号改变癌细胞的代谢。然而，肿瘤细胞的代谢调节是否以及如何反馈影响肿瘤进展还不太清楚。目前还不清楚癌细胞如何协调两种主要代谢途径（糖酵解和β-内酰胺分解）之间的变化。我们观察到PKM 2定位于细胞核。核PKM 2作为转录共激活因子激活基因转录。更重要的是，PKM2，一种关键的糖酵解酶，作为一种蛋白激酶，在Y705磷酸化stat3，从而激活基因转录。我们的实验证明PKM 2的蛋白激酶活性介导PKM 2促进细胞增殖的作用。此外，我们的研究表明，PKM2上调转氨酶的表达，表明癌细胞代谢和细胞增殖之间的反馈回路，以及这种糖酵解酶在协调糖酵解和转氨酶解的变化中的潜在功能。该研究项目的目的是了解PKM2在肿瘤进展中的作用。我们提出了三个具体的目标来测试我们的假设，PKM2，糖酵解酶，促进细胞增殖和肿瘤的进展，不仅通过调整糖酵解代谢物的流动有利于生物合成，而且还通过调节β-氨基丁酸。通过 PKM 2参与多种不同的代谢过程，在肿瘤进展过程中协调代谢改变和细胞增殖。该项目中提出的实验将首先测试PKM 2是否确实激活谷氨酰胺分解。在第二个具体目标中提出的实验将解决PKM2是否也在体内发生对多巴胺分解的激活。在具体的目标3中，我们将阐明生长信号如何影响PKM 2在激活β-内酰胺分解中的功能。我们的研究最终将应用于 癌症治疗新策略的发展。

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.