PKM2 coordinates glycolysis and glutaminolysis in cancer cells

PKM2 协调癌细胞中的糖酵解和谷氨酰胺分解

• 批准号: 8788258
• 负责人: Zhi-Ren Liu
• 金额: $ 16.1万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788258
• 关键词: Achievement; Address; Affect; Anabolism; Blood Circulation; Carbon; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Clinical; Development; Enzymes; Feedback; Genetic Transcription; Glutaminase; Glutamine; Glycolysis; Glycolysis Pathway; Goals; Growth; Growth Factor; Health; Isoenzymes; M2 protein; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Nuclear; Nutrient; Oncogenic; PC3 cell line; Pathway interactions; Phase; Play; Process; Production; Proliferating; Protein Kinase; Proteins; Pyruvate Kinase; Regulation; Research Project Grants; Role; Route; SW480; SW620; Signal Transduction; Source; Testing; addiction; base; cancer cell; cancer therapy; follow-up; in vivo; inhibitor/antagonist; inorganic phosphate; mutant; neoplastic cell; nutrition; research study; tumor growth; tumor metabolism; tumor progression; tumor xenograft; uptake; vector

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.

描述（由申请人提供）：有充分的文献证明致癌产物和生长信号改变癌细胞的代谢。然而，人们对肿瘤细胞的代谢调节是否以及如何反馈影响肿瘤进展知之甚少。癌细胞如何协调糖酵解和谷氨酰胺解这两种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PKM2作为转录共激活因子激活基因转录。更重要的是，PKM2，一个关键的糖酵解酶，作为一个蛋白激酶磷酸化stat3在Y705，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PKM2促进细胞增殖的作用。此外，我们的研究发现PKM2上调谷氨酰胺酶的表达，表明癌细胞代谢和细胞增殖之间存在反馈回路，并且该糖酵解酶在协调糖酵解和谷氨酰胺酶的变化方面具有潜在的功能。本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PKM2，一种糖酵解酶，不仅通过调节糖酵解代谢产物的流动，有利于生物合成，而且通过调节谷氨酰胺水解，促进细胞增殖和肿瘤进展。通过