Cancer cell survival during factor deprivation

因子剥夺期间癌细胞的存活

基本信息

批准号：
8287648
负责人：
CRAIG B THOMPSON
金额：
$ 35.52万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8287648
关键词：
ATP Citrate (pro-S)-Lyase Acetyl Coenzyme A Acetylglucosamine Affect Ammonia Anabolism Apoptosis Apoptotic Biguanides Binding Bioenergetics Cancer Cell Growth Catabolism Cell Cycle Arrest Cell Death Cell Proliferation Cell Survival Cells Cessation of life Chemicals Citrates Citric Acid Cycle Culture Media Cytoplasm Data Dependence Development Embryo Enhancers Enzymes Event Exhibits Failure Fatty Acids Fibroblasts Five-Year Plans Gene Expression Genes Genetic Determinism Glucose Glutamine Glycolysis Grant Growth Growth Factor Health Hematopoietic stem cells Hexosamines Human In Vitro Investigation Laboratories Lead Link Lipids Malignant Neoplasms Mammalian Cell Mediating Metabolic Metabolism Metformin Mitochondria Modification Molecular Mutation NADP Necrosis Non-Essential Amino Acid Normal Cell Nuclear Nuclear Proteins Nucleotide Biosynthesis Nutrient Oncogenes Oncogenic Organelles Oxaloacetates Pathway interactions Pentosephosphate Pathway Phenformin Phospholipids Phosphotransferases Play Production Proliferating Protein Biosynthesis Protein Isoforms Proteins Pyruvate Pyruvate Kinase RNA Interference RNA chemical synthesis Regulation Reporting Resistance Ribose Ribosomes Role Saturated Fatty Acids Serum Signal Pathway Signal Transduction Site Stearoyl-CoA Desaturase Testing Therapeutic Toxic effect Toxin Wild Type Mouse Work addiction aerobic glycolysis base blood glucose regulation c-myc Genes cancer cell cancer therapy cell growth cell transformation chemotherapeutic agent deprivation design enzyme pathway extracellular glucosamine 6-phosphate glucose metabolism glucose uptake glycosylation in vivo inhibitor/antagonist lipid biosynthesis nucleotide metabolism oxidation pi bond promoter research study response uptake

项目摘要

DESCRIPTION (provided by applicant): Over the last decade, work from a number of laboratories has established that mammalian cells depend on growth factor-dependent signaling to maintain their viability. We have demonstrated that this is true even for cells that lack the ability to initiate their own demise through the intrinsic apoptotic pathway. This finding led us to hypothesize that the essential function of survival signaling is to direct the cell to take up and metabolize sufficient nutrients to maintain mitochondrial integrity and cellular ATP production. The ability of cancer cells to survive in the absence of growth factor signaling depends on the cells acquiring mutations that stimulate sufficient nutrient uptake and metabolism to maintain cellular bioenergetics. Such signaling renders a cancer cell resistant to cell death by either apoptosis or necrosis. In the preceding five years of this grant, we established that Akt activation promotes cell survival by stimulating glucose uptake and metabolism. As a result, Akt-transformed cells become addicted to glycolytic metabolism for the support of ATP production. In addition, we have defined that glutamine represents a second essential metabolic substrate required for cell proliferation of transformed cells. In contrast to glucose, glutamine uptake and metabolism is not regulated by Akt-dependent signal transduction. In the ensuing five years, we plan to further investigate the regulation of glucose and/or glutamine uptake in normal and transformed cells. We believe a more complete characterization of the essential role of these nutrients in cancer cell growth and survival may lead to the development of new and safer cancer therapies. Three Specific Aims are envisioned. We will: 1) Examine whether Akt-induced reprogramming of glucose metabolism can be exploited to selectively impair cancer cell growth and/or survival. 2) Define the molecular determinants of the glutamine dependence exhibited by some transformed cells. 3) Investigate the signaling pathways that can induce a transition from glucose-dependent mitochondrial metabolism to a glutamine-dependent mitochondrial metabolism during growth of normal and/or transformed cells. PUBLIC HEALTH RELEVANCE: Mammalian cells depend on extracellular signals to direct their nutrient uptake and metabolism. Recent evidence suggests that distinct oncogenic mutations control the cellular metabolism of glucose and glutamine, the two major nutrients used by cancer cells to fuel their growth and proliferation. This project seeks to determine whether oncogenic reprogramming of metabolism can be exploited to develop new cancer therapeutic strategies.

描述（由申请人提供）：在过去的十年中，许多实验室的工作已经确定哺乳动物细胞依赖生长因子依赖性信号传导来维持其活力。我们已经证明，即使对于缺乏通过内在凋亡途径启动自身死亡能力的细胞来说也是如此。这一发现使我们推测生存信号的基本功能是指导细胞吸收和代谢足够的营养物质以维持线粒体的完整性和细胞 ATP 的产生。癌细胞在缺乏生长因子信号传导的情况下生存的能力取决于细胞获得突变，刺激足够的营养吸收和代谢以维持细胞生物能。这种信号传导使癌细胞能够抵抗细胞凋亡或坏死引起的细胞死亡。在这项资助的前五年中，我们确定 Akt 激活通过刺激葡萄糖摄取和代谢来促进细胞存活。结果，Akt 转化的细胞变得沉迷于糖酵解代谢，以支持 ATP 的产生。此外，我们还定义谷氨酰胺代表转化细胞的细胞增殖所需的第二种重要代谢底物。与葡萄糖相反，谷氨酰胺的摄取和代谢不受 Akt 依赖性信号转导的调节。在接下来的五年中，我们计划进一步研究正常细胞和转化细胞中葡萄糖和/或谷氨酰胺摄取的调节。我们相信，更完整地描述这些营养素在癌细胞生长和存活中的重要作用可能会导致新的、更安全的癌症疗法的开发。设想了三个具体目标。我们将： 1) 检查 Akt 诱导的葡萄糖代谢重编程是否可用于选择性损害癌细胞生长和/或存活。 2) 定义一些转化细胞表现出的谷氨酰胺依赖性的分子决定因素。 3) 研究在正常和/或转化细胞生长过程中可诱导从葡萄糖依赖性线粒体代谢转变为谷氨酰胺依赖性线粒体代谢的信号传导途径。公共健康相关性：哺乳动物细胞依靠细胞外信号来指导其营养吸收和代谢。最近的证据表明，不同的致癌突变控制着葡萄糖和谷氨酰胺的细胞代谢，这是癌细胞用来促进其生长和增殖的两种主要营养物质。该项目旨在确定是否可以利用致癌的代谢重编程来开发新的癌症治疗策略。