Is GLUT1 required for tumor growth and the Warburg Effect?

肿瘤生长和瓦尔堡效应需要 GLUT1 吗？

• 批准号: 8188853
• 负责人: STEVEN M ANDERSON
• 金额: $ 18.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8188853
• 关键词: 1-Phosphatidylinositol 3-Kinase; ATP Synthesis Pathway; Address; Affect; Agar; Alleles; Apoptosis; Appearance; Autophagocytosis; Bioenergetics; Burn injury; Carbon; Cell Death; Cell Line; Cell Proliferation; Cell surface; Cells; Cessation of life; Chemicals; Complement; Consumption; Data; Development; Energy-Generating Resources; Environment; Epithelial Cells; Event; Exhibits; Face; Failure; Fatty acid glycerol esters; Gene Expression Profiling; Generations; Genes; Genetic Recombination; Glucose; Glucose Transporter; Glycolysis; Goals; Growth; Hexose Transporter; In Vitro; Lead; Mammary Tumorigenesis; Mammary gland; Metabolic; Metabolic Pathway; Metabolism; Methods; Monitor; Mouse Mammary Tumor Virus; Mus; Mutation; Oncogenes; Pathway interactions; Pharmaceutical Preparations; Physiology; Polyomavirus; Process; SLC2A1 gene; Source; Staging; Therapeutic; Tissues; Transgenes; Transgenic Mice; Viral Tumor Antigens; Warburg Effect; aerobic glycolysis; cancer cell; fatty acid oxidation; flexibility; glucose transport; glucose uptake; human FRAP1 protein; in vivo; inhibitor/antagonist; insight; interest; killings; meetings; neoplastic cell; overexpression; prevent; recombinase; research study; sugar; therapeutic target; therapy development; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Tumors and tumor cells exhibit a unique metabolism referred to as the Warburg Effect characterized by high rates of glucose transport and glycolysis. Glycolysis is an inefficient means by which to generate ATP, however since this change is almost universal in its appearance it must provide a selective advantage to tumor cells. Tumor cells must transport large amounts of glucose to generate the needed ATP. Most tumor cells have elevated levels of the glucose transporter GLUT1 which is thought to be responsible for the increased glucose transport needed to drive the synthesis of ATP by glycolysis. The use of glucose by tumor cells is highly leveraged because it is a critical substrate. The overall goal of this proposal is to determine whether glucose transported into tumor cells via hexose transporters represents the major metabolic event that supports altered tumor metabolism in vivo. We hypothesize that glucose is the major metabolic precursor that supports the Warburg Effect, and therefore loss of hexose transporters will suppress tumor cell proliferation in vivo. Furthermore failure to meet the metabolic needs of the tumor due to loss of GLUT1 expression will result in cell death by either apoptosis or induction of autophagy which in turn leads to cell death. It may be possible that tumor cells escape this fate by mutation of oncogenes that modulate tumor metabolism or altering the expression of metabolic genes that compensate for the loss of glucose as a carbon source for bioenergetic and biosynthetic processes and we will characterize these compensatory pathways. Preliminary data shows that knockdown of GLUT1 reduces glucose uptake and consumption, lactate generation, and proliferation in vitro and in vivo. Overexpression of GLUT1 enhances glucose uptake and consumption, lactate generation, suppresses apoptosis, and stimulates tumor growth in vivo. We propose three aims: 1) Determine what hexose transporters are functional in cells lacking GLUT1, determine how loss of these additional hexose transporters affects tumor cell proliferation in vitro and in vivo, and determine the contributions of other metabolic pathways (fatty acid oxidation and glutaminolysis) to tumor cell metabolism; 2) Identify genes that support the proliferation of tumor cells lacking GLUT1 using a synthetic lethal screen; and 3) Determine whether elimination of GLUT1 from mammary epithelial cells in vivo alters mammary tumorigenesis induced by ErbB2. Gene expression profiling and deep sequencing will identify genetic changes that support tumor growth in the absence of GLUT1. These specific aims will provide insight into the critical molecules that regulate glucose uptake, how tumor cells compensate for the loss of glucose as a metabolite, whether the metabolic environment stimulates genetic changes in tumors, and whether GLUT1 is required for induction of mammary tumorigenesis. Given the current interest in developing therapies that attack the metabolism of tumor cells, these studies are timely and will provide important insight into the plasticity of tumor metabolism and the genetic changes that underlie tumor adaption to the metabolic challenges it faces. PUBLIC HEALTH RELEVANCE: Tumor cells grow and divide quickly and thus require abundant energy; however, tumor cells frequently generate energy from sugar (specifically glucose), which is less efficient than burning fat. As a result they consume high amounts of glucose, and rely on one cell surface transporter to bring in the fuel they need. We wish to determine how limiting glucose entry into tumor cells affects their growth, and identify how cancer cells compensate for the lack of glucose when they continue to survive and grow. These insights may provide new means to kill tumor cells by blocking the different chemical ways they use to make energy.

描述（由申请人提供）：肿瘤和肿瘤细胞表现出一种独特的代谢，称为Warburg效应，其特征是高速率的葡萄糖转运和糖酵解。糖酵解是一种低效的产生ATP的方法，然而，由于这种变化在其外观上几乎是普遍的，它必须为肿瘤细胞提供选择性优势。肿瘤细胞必须运输大量的葡萄糖来产生所需的ATP。大多数肿瘤细胞的葡萄糖转运蛋白GLUT1水平升高，这被认为是葡萄糖转运增加的原因，葡萄糖转运需要通过糖酵解来驱动ATP的合成。肿瘤细胞高度利用葡萄糖，因为它是一种关键的底物。本提案的总体目标是确定葡萄糖通过己糖转运体转运到肿瘤细胞中是否代表了支持体内肿瘤代谢改变的主要代谢事件。我们假设葡萄糖是支持Warburg效应的主要代谢前体，因此体内己糖转运体的缺失会抑制肿瘤细胞的增殖。此外，由于GLUT1表达缺失而不能满足肿瘤的代谢需要，会导致细胞凋亡或诱导自噬，进而导致细胞死亡。肿瘤细胞可能通过调节肿瘤代谢的癌基因突变或改变代谢基因的表达来逃避这种命运，代谢基因补偿了作为生物能量和生物合成过程碳源的葡萄糖的损失，我们将描述这些补偿途径。