Role of the pentose phosphate pathway in tumorigenesis

磷酸戊糖途径在肿瘤发生中的作用

基本信息

批准号：
9236169
负责人：
Xiaolu Yang
金额：
$ 21.01万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9236169
关键词：
Address Anabolism Antioxidants Applications Grants Binding Cell Proliferation Cell Proliferation Regulation Cells Consumption Development Dimerization Drug Metabolic Detoxication Drug Targeting Enzymes Exhibits Genes Genetic Transcription Glucose Glucosephosphate Dehydrogenase Glycolysis Homologous Gene Human Hyperactive behavior Impairment Light Link Maintenance Malignant neoplasm of ovary Metabolic Metabolic Pathway Metabolism Modeling Mutate Mutation NADP Neoplasm Metastasis Normal Cell Oncogenes Oncogenic Oxidative Stress Oxygen Pathway interactions Pentosephosphate Pathway Process Production Protein Family Protein Isoforms Protein p53 Proteins Reactive Oxygen Species Reducing Agents Regulation Research Ribose Role Source System TP53 gene Therapeutic Tumor Biology Tumor Suppressor Proteins Tumorigenicity Up-Regulation Warburg Effect aerobic glycolysis blood glucose regulation cancer cell cancer therapy cell growth cell transformation dimer driving force enzyme pathway glucose metabolism improved insight macromolecule mutant neoplastic cell novel novel therapeutics nucleotide metabolism overexpression prevent protein protein interaction public health relevance response targeted cancer therapy therapeutic target tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): This application seeks to define the regulation of the pentose phosphate pathway (PPP) by p53 family proteins, and the role of this metabolic pathway in tumorigenesis. Cancer cells are markedly different from normal cells in their metabolism. This metabolic reprogramming meets the demand of cancer cells for rapid production of macromolecules and effective detoxification of reactive oxygen species (ROS). Both macromolecule biosynthesis and ROS detoxification require NADPH (nicotinamide adenine dinucleotide phosphate, reduced), the intracellular reducing equivalent. NADPH is used in reductive biosynthetic processes and is also the ultimate reducing agent for various anti-oxidant systems. A major source of NADPH is the PPP, a glucose metabolic pathway that also provides cells with ribose for de novo nucleotide synthesis. Our preliminary results revealed that the PPP is regulated by both p53 and its structural homologue, TAp73. p53 is a preeminent tumor suppressor, and it is the most frequently mutated gene in human tumors. Nevertheless, how p53 prevents tumor formation is not well understood, and remains a central issue in tumor biology. In contrast to p53, TAp73 is rarely mutated in human tumors, and instead is often over-expressed. It is unclear whether TAp73 affords an advantage to tumor cells and if so, what the underlying mechanism may be. We have found that p53 directly binds to and inactivates glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. Through this inhibition, p53 regulates glucose metabolism, NADPH production, and biosynthesis. We have also shown that TAp73 supports tumor cell proliferation. Mechanistically, TAp73 enhances the expression of the G6PD gene, increases PPP flux, and directs glucose to the production of NADPH and ribose, for the synthesis of macromolecules and detoxification of ROS. Together, these findings shed important light on the roles of p53 and TAp73 in metabolism and proliferation. They also suggest that the PPP may be a focal point of regulation for cell proliferation and a valuable target for cancer therapy. We plan to further investigate the regulation of G6PD by p53 and TAp73, and role of the G6PD and the PPP in tumorigenesis. Our central hypothesis is that the regulation of G6PD by p53 and TAp73 is important for controlling biosynthesis and anti-oxidant response, and a hyperactive PPP due to p53 inactivation and TAp73 up-regulation contributes to tumorigenesis. We propose three specific aims: 1) Elucidate the mechanisms by which p53 and TAp73 regulate G6PD, 2) Define the activity of G6PD in oncogenic transformation, and 3) Determine the role of G6PD in the progression of cancer. The proposed studies will significantly improve our understanding of the functions of the p53 family proteins and the metabolic reprogramming in tumor cells. They will also likely provide a rationale for targeting p53- and TAp73-regulated metabolic enzymes as a new therapy for cancer.

描述（由应用程序提供）：本应用程序旨在通过p53家族蛋白定义五磷酸途径（PPP）的调节，以及该代谢途径在肿瘤发生中的作用。癌细胞在代谢中与正常细胞明显不同。这种代谢重编程满足了癌细胞快速产生大分子的需求以及活性氧（ROS）的有效排毒。大分子生物合成和ROS解毒都需要NADPH（烟酰胺腺苷二核苷酸磷酸盐，还原），细胞内还原等效剂。 NADPH用于减少生物合成过程，也是各种抗氧化剂系统的最终还原剂。 NADPH的主要来源是PPP，PPP是一种葡萄糖代谢途径，它还为细胞提供了从头核苷酸合成的核糖。我们的初步结果表明，PPP受p53及其结构同源物TAP73的调节。 p53是一种杰出的肿瘤抑制剂，它是人类肿瘤中最常见的突变基因。然而，p53如何防止肿瘤的形成尚不清楚，并且仍然是肿瘤生物学的核心问题。与p53相反，TAP73在人类肿瘤中很少突变，而是经常表达过表达。目前尚不清楚TAP73是否对肿瘤细胞有优势，如果是，那么基本机制可能是什么。我们发现p53直接与PPP的速率限制酶（G6PD）直接结合并灭活葡萄糖-6-磷酸脱氢酶（G6PD）。通过这种抑制作用，p53调节葡萄糖代谢，NADPH产生和生物合成。我们还表明，TAP73支持肿瘤细胞增殖。从机械上讲，TAP73增强了G6PD基因的表达，增加了PPP通量，并将葡萄糖引导至NADPH和核糖的产生，以合成大分子的合成和ROS的排毒。这些发现一起，对p53和TAP73在代谢和增殖中的作用阐明了重要的启示。他们还建议PPP可能是细胞增殖的调节焦点，也是癌症治疗的宝贵靶标。我们计划进一步研究P53和TAP73对G6PD的调节，以及G6PD和PPP在肿瘤发生中的作用。我们的中心假设是，p53和TAP73对G6PD的调节对于控制生物合成和抗氧化反应很重要，并且由于p53失活而引起的过度活跃PPP和TAP73上调有助于肿瘤造成肿瘤。我们提出了三个具体目标：1）阐明p53和TAP73调节G6PD的机制，2）定义G6PD在致癌转化中的活性，3）确定G6PD在癌症进展中的作用。拟议的研究将显着提高我们对p53家族蛋白功能和肿瘤细胞中代谢重编程的理解。他们还可能会为靶向P53和TAP73调节的代谢酶作为癌症的新疗法提供理由。