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: 8333385
• 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/8333385
• 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.

描述（由申请人提供）：肿瘤和肿瘤细胞表现出独特的新陈代谢，称为WARBURG效应，其特征在于葡萄糖转运和糖酵解的速率高。糖酵解是产生ATP的一种低效手段，但是由于这种变化的外观几乎是普遍的，因此必须为肿瘤细胞提供选择性的优势。肿瘤细胞必须运输大量葡萄糖以产生所需的ATP。大多数肿瘤细胞的葡萄糖转运蛋白glut1水平升高，这被认为是通过糖酵解驱动ATP合成所需的葡萄糖转运增加的原因。肿瘤细胞对葡萄糖的使用高度杠杆化，因为它是关键的底物。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，因此己糖转运蛋白的丧失将抑制体内肿瘤细胞的增殖。此外，由于缺失GLUT1表达而无法满足肿瘤的代谢需求，将导致细胞凋亡或自噬诱导自动噬，这又导致细胞死亡。肿瘤细胞可能通过调节肿瘤代谢的癌基因的突变或改变代谢基因的表达来避免这种命运，从而补偿葡萄糖作为生物能和生物合成过程的碳源，我们将表征这些补偿性途径。 初步数据表明，GLUT1的敲低可减少体外和体内的葡萄糖摄取和消耗，乳酸产生和增殖。 GLUT1的过表达可增强葡萄糖摄取和消耗，乳酸产生，抑制凋亡并刺激体内肿瘤的生长。我们提出了三个目的：1）确定哪些己糖转运蛋白在缺乏GLUT1的细胞中起作用，确定这些额外的己糖转运蛋白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）对肿瘤细胞生成的贡献； 2）确定支持使用合成致死筛查缺乏GLUT1的肿瘤细胞增殖的基因； 3）确定在体内消除乳腺上皮细胞中的GLUT1是否会改变ERBB2诱导的乳腺肿瘤发生。基因表达分析和深度测序将确定在没有GLUT1的情况下支持肿瘤生长的遗传变化。这些具体目的将提供对调节葡萄糖摄取的关键分子的见解，肿瘤细胞如何补偿葡萄糖作为代谢产物的丧失，代谢环境是否刺激肿瘤的遗传变化以及是否需要GLUT1诱导乳腺肿瘤。鉴于目前对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面临的代谢挑战的基础的遗传变化提供重要的见解。