Role of the pentose phosphate pathway in tumorigenesis

磷酸戊糖途径在肿瘤发生中的作用

• 批准号: 9101315
• 负责人: Xiaolu Yang
• 金额: $ 17.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/9101315
• 关键词: Address; Anabolism; Antioxidants; Applications Grants; Binding; Cell Proliferation; Cell Proliferation Regulation; Cells; Consumption; Development; Drug Metabolic Detoxication; Drug Targeting; Enzymes; Exhibits; Genes; Genetic Transcription; Glucose; Glucosephosphate Dehydrogenase; Glycolysis; Homologous Gene; Human; Light; Link; Maintenance; Malignant Neoplasms; 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; Up-Regulation; Warburg Effect; aerobic glycolysis; cancer cell; cancer therapy; cell growth; cell transformation; dimer; driving force; glucose metabolism; improved; insight; macromolecule; meetings; 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

 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）：本申请旨在确定p53家族蛋白对磷酸戊糖途径（PPP）的调节，以及该代谢途径在肿瘤发生中的作用。癌细胞在代谢方面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（还原型烟酰胺腺嘌呤二核苷酸磷酸），即细胞内的还原等价物。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。NADPH的主要来源是PPP，这是一种葡萄糖代谢途径，也为细胞提供核糖用于从头核苷酸合成。 我们的初步结果表明，PPP是由p53和它的结构同源物，TAp 73。p53是一种重要的肿瘤抑制基因，也是人类肿瘤中最常发生突变的基因。然而，p53如何防止肿瘤形成还没有很好的理解，仍然是肿瘤生物学的中心问题。与p53相反，TAp 73在人类肿瘤中很少突变，而是经常过度表达。目前还不清楚TAp 73是否为肿瘤细胞提供了优势，如果是这样，潜在的机制可能是什么。我们已经发现，p53直接结合并灭活葡萄糖-6-磷酸脱氢酶（G6 PD），PPP的限速酶。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TAp 73支持肿瘤细胞增殖。在机制上，TAp 73增强G6 PD基因的表达，增加PPP通量，并指导葡萄糖产生NADPH和核糖，用于大分子的合成和ROS的解毒。总之，这些发现揭示了p53和TAp 73在代谢和增殖中的作用。他们还表明PPP可能是细胞增殖调节的焦点和癌症治疗的有价值的靶点。 我们计划进一步研究p53和TAp 73对G6 PD的调控，以及G6 PD和PPP在肿瘤发生中的作用。我们的中心假设是，通过p53和TAp 73调节G6 PD对于控制生物合成和抗氧化反应是重要的，并且由于p53失活和TAp 73上调而导致的过度活跃的PPP有助于肿瘤发生。我们提出了三个具体的目标：1）阐明p53和TAp 73调节G6 PD的机制，2）确定G6 PD在致癌转化中的活性，3）确定G6 PD在癌症进展中的作用。这些研究将显著提高我们对p53家族蛋白的功能和肿瘤细胞中代谢重编程的理解。它们也可能为靶向p53和TAp 73调节的代谢酶作为癌症的新疗法提供理论基础。