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（由申请方提供）：肿瘤和肿瘤细胞表现出称为瓦尔堡效应的独特代谢，其特征在于高速率的葡萄糖转运和糖酵解。糖酵解是产生ATP的低效手段，然而，由于这种变化在其外观上几乎是普遍的，因此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以产生所需的ATP。大多数肿瘤细胞具有升高水平的葡萄糖转运蛋白GLUT 1，其被认为是负责增加葡萄糖转运，所述葡萄糖转运需要通过糖酵解驱动ATP的合成。肿瘤细胞对葡萄糖的利用是高度杠杆化的，因为它是一种关键底物。本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尔堡效应的主要代谢前体，因此己糖转运蛋白的丢失将抑制体内肿瘤细胞增殖。此外，由于GLUT 1表达的丧失而不能满足肿瘤的代谢需要将通过细胞凋亡或诱导自噬而导致细胞死亡，这反过来又导致细胞死亡。肿瘤细胞可能通过调节肿瘤代谢的癌基因突变或改变代谢基因的表达来逃避这种命运，这些代谢基因补偿葡萄糖作为生物能量和生物合成过程的碳源的损失，我们将描述这些补偿途径。 初步数据显示，GLUT 1的敲低降低了体外和体内葡萄糖摄取和消耗、乳酸产生和增殖。GLUT 1的过表达增强葡萄糖摄取和消耗、乳酸产生、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GLUT 1的细胞中起作用，确定这些额外的己糖转运蛋白的损失如何影响体外和体内肿瘤细胞增殖，并确定其他代谢途径的贡献2）使用合成致死筛选鉴定支持缺乏GLUT 1的肿瘤细胞增殖的基因;和3）确定体内从乳腺上皮细胞中消除GLUT 1是否改变ErbB 2诱导的乳腺肿瘤发生。基因表达谱分析和深度测序将确定在GLUT 1缺乏的情况下支持肿瘤生长的遗传变化。这些特定的目标将提供洞察调节葡萄糖摄取的关键分子，肿瘤细胞如何补偿葡萄糖作为代谢物的损失，代谢环境是否刺激肿瘤的遗传变化，以及GLUT 1是否是诱导乳腺肿瘤发生所必需的。鉴于目前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和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。 公共卫生相关性：肿瘤细胞生长和分裂迅速，因此需要大量的能量;然而，肿瘤细胞经常从糖（特别是葡萄糖）中产生能量，这比燃烧脂肪效率低。因此，它们消耗大量的葡萄糖，并依赖于一种细胞表面转运蛋白来运送它们所需的燃料。我们希望确定限制葡萄糖进入肿瘤细胞如何影响其生长，并确定癌细胞在继续生存和生长时如何补偿葡萄糖的缺乏。这些见解可能会提供新的方法，通过阻断肿瘤细胞产生能量的不同化学途径来杀死肿瘤细胞。