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（由申请人提供）：本申请旨在明确p53家族蛋白对戊糖磷酸途径（PPP）的调节，以及该代谢途径在肿瘤发生中的作用与正常细胞的代谢显着不同。重编程满足癌细胞快速产生大分子和有效解毒活性氧（ROS）的需求，大分子生物合成和ROS解毒都需要NADPH。（还原的烟酰胺腺嘌呤二核苷酸磷酸），细胞内还原性 NADPH 用于还原性生物合成过程，也是各种抗氧化系统的最终还原剂。 PPP 是一种葡萄糖代谢途径。为细胞提供核糖以进行核苷酸的从头合成。我们的初步结果表明，PPP 受到 p53 及其结构同源物 TAp73 的调节，p53 是一种卓越的肿瘤抑制基因，并且它是人类肿瘤中最常见的突变基因，然而，p53 如何预防肿瘤形成尚不清楚。与p53相比，TAp73在人类肿瘤中很少发生突变，并且经常过度表达，目前尚不清楚。为肿瘤细胞提供优势，如果是的话，其潜在机制可能是什么。我们发现 p53 直接结合并灭活 PPP 的限速酶， p53 调节葡萄糖代谢、NADPH 产生和生物合成。从机制上讲，TAp73 可以增强 G6PD 的表达。这些发现为 p53 和 TAp73 在代谢和增殖中的作用提供了重要的线索。 PPP可能是细胞增殖调节的焦点，也是癌症治疗的重要靶点。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。 p53 失活和 TAp73 上调导致的过度活跃的 PPP 有助于肿瘤发生：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，以及3）确定G6PD在癌症进展中的作用所提出的研究将显着提高我们对p53功能的理解。它们还可能为靶向 p53 和 TAp73 调节的代谢酶作为癌症的新疗法提供理论基础。