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: 8505396
• 负责人: STEVEN M ANDERSON
• 金额: $ 17.09万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505396
• 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; deep sequencing; 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; tumor metabolism; 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.

描述（由申请人提供）：肿瘤和肿瘤细胞表现出一种被称为瓦伯格效应的独特代谢，其特征是葡萄糖转运和糖酵解的高速率。糖酵解是产生 ATP 的低效方法，然而，由于这种变化在其外观上几乎是普遍存在的，因此它必须为肿瘤细胞提供选择性优势。肿瘤细胞必须转运大量葡萄糖才能产生所需的 ATP。大多数肿瘤细胞的葡萄糖转运蛋白 GLUT1 水平升高，该转运蛋白被认为负责通过糖酵解驱动 ATP 合成所需的葡萄糖转运增加。肿瘤细胞对葡萄糖的利用受到高度重视，因为它是一种关键的底物。该提案的总体目标是确定通过己糖转运蛋白转运到肿瘤细胞中的葡萄糖是否代表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瓦伯格效应的主要代谢前体，因此己糖转运蛋白的损失将抑制体内肿瘤细胞的增殖。此外，由于 GLUT1 表达缺失而无法满足肿瘤的代谢需求，将导致细胞凋亡或诱导自噬而死亡，进而导致细胞死亡。肿瘤细胞有可能通过调节肿瘤代谢的癌基因突变或改变补偿葡萄糖作为生物能和生物合成过程碳源的损失的代谢基因的表达来逃脱这种命运，我们将描述这些补偿途径。 初步数据表明，敲除 GLUT1 可减少体内外葡萄糖的摄取和消耗、乳酸生成以及增殖。 GLUT1 的过度表达可增强葡萄糖的摄取和消耗、乳酸的生成、抑制细胞凋亡并刺激体内肿瘤生长。我们提出三个目标：1）确定哪些己糖转运蛋白在缺乏 GLUT1 的细胞中发挥功能，确定这些额外的己糖转运蛋白的缺失如何影响体外和体内肿瘤细胞的增殖，并确定其他代谢途径（脂肪酸氧化和谷氨酰胺分解）的贡献) 影响肿瘤细胞代谢； 2) 使用合成致死筛选来鉴定支持缺乏 GLUT1 的肿瘤细胞增殖的基因； 3)确定从体内乳腺上皮细胞消除GLUT1是否会改变ErbB2诱导的乳腺肿瘤发生。基因表达谱和深度测序将识别在缺乏 GLUT1 的情况下支持肿瘤生长的基因变化。这些具体目标将深入了解调节葡萄糖摄取的关键分子、肿瘤细胞如何补偿作为代谢物的葡萄糖的损失、代谢环境是否刺激肿瘤的遗传变化，以及诱导乳腺肿瘤发生是否需要 GLUT1。鉴于目前人们对开发攻击肿瘤细胞代谢的疗法的兴趣，这些研究是及时的，将为肿瘤代谢的可塑性以及肿瘤适应其所面临的代谢挑战的遗传变化提供重要的见解。