p53-GAMT pathway in cancer cell metabolism and DNA damage-induced carcinogenesis

p53-GAMT 通路在癌细胞代谢和 DNA 损伤诱发癌变中的作用

基本信息

批准号：
8629620
负责人：
SAM W LEE
金额：
$ 32.77万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-13 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8629620
关键词：
Anabolism Apoptosis Autophagocytosis Cancer Biology Cancer Etiology Cell Death Cell Survival Cell physiology Cells Cellular Stress Response Cessation of life Characteristics Consumption Creatine DNA Damage Decision Making Development Energy Metabolism Energy-Generating Resources Enzymes Exposure to Gene Targeting Genotoxic Stress Glucose Glycolysis Goals Guanidinoacetate N-Methyltransferase Homeostasis Knockout Mice Link Malignant - descriptor Malignant Neoplasms Mediating Metabolic Metabolic stress Metabolism Mitochondria Nutrient Oxygen Consumption Pathway interactions Play Process Production Protein p53 Recovery Regulation Respiration Role Signal Transduction Starvation Stress Tissues Tumor Suppressor Proteins Up-Regulation Warburg Effect base biological adaptation to stress cancer cell carcinogenesis conventional therapy deprivation fatty acid oxidation gene function glucose metabolism in vivo novel public health relevance response tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cancer cells have enhanced glycolysis and show lower oxygen consumption, indicating a shift to glycolysis for the production of energy, thereby contributing to the metabolic change known as Warburg effect, which is characteristic of virtually all cancers. Many mysteries remain unsolved in our understanding of cancer cell metabolism. Recent discoveries indicate that tumor suppressor p53 has much broader cellular functions, such as regulating glucose metabolism and mitochondrial respiration. We identified GAMT/guanidinoacetate methyltransferase, an enzyme involved in creatine synthesis metabolism as a novel p53 target gene, and a key downstream effector of the adaptive response to DNA damage and nutrient stress in cancer cels. We reveal that GAMT is involved in p53-dependent apoptosis in response to DNA damage/genotoxic stress, and also demonstrate that the GAMT pathway plays an essential role in the regulation of ATP homeostasis during nutrient stress. Surprisingly, we also found that p53->GAMT up-regulates fatty acid oxidation (FAO) induced by DNA damage stress or glucose starvation, facilitating the use of this pathway as an alternative ATP-generating energy source when glucose is scarce. The main goal of this application is to understand the underlying mechanisms for the unusual effect of the p53-GAMT-Creatine pathway in DNA damage-mediated carcinogenesis, as well as in cancer cell metabolism. The specific aims are to (1) investigate the underlying mechanism(s) for the substitutive effects of the p53-GAMT-Creatine pathway in energy metabolism in cancer cells; (2) define the role of this pathway in regulating DNA damage responses (cell fate decision; cell death or survival) in cancer cells; and (3) determine the function of GAMT in metabolic and DNA damage stress responses using mouse knock-out approaches. Our findings of the p53->GAMT-Creatine pathway represent a new link between cellular stress responses and the metabolic processes of creatine synthesis and FAO, providing implications for understanding selective nutrient adaptation and how this might impact cancer development and responses to conventional therapies. The proposed studies are highly relevant for cancer biology, as they will reveal how metabolic changes impact cancer and how this newly discovered pathway is emerging as a key contributor to tumorigenesis/carcinogenesis.

描述（由申请人提供）：癌细胞增强了糖酵解并显示出较低的氧气消耗，表明向能量生产的糖酵解转移，从而有助于代谢变化称为沃堡效应，这实际上是所有癌症的特征。在我们对癌细胞代谢的理解中，许多谜团仍未解决。最近的发现表明抑制肿瘤p53具有更广泛的细胞功能，例如调节葡萄糖代谢和线粒体呼吸。我们将GAMT/鸟尼二乙酸甲基转移酶，一种参与肌酸合成代谢的酶是一种新型的p53靶基因，也是对DNA损伤和癌症中营养应激的自适应反应的关键下游效应。我们揭示了GAMT响应DNA损伤/遗传毒性应激而参与p53依赖性细胞凋亡，并且还证明了GAMT途径在养分胁迫期间的ATP稳态调节中起着至关重要的作用。令人惊讶的是，我们还发现，p53-> gamt上调了DNA损伤应激或葡萄糖饥饿引起的脂肪酸氧化（FAO），当葡萄糖稀缺时，促进了该途径作为另一种ATP生成能源的使用。该应用的主要目的是了解p53-Gamt-recreatine途径在DNA损伤介导的癌变以及癌细胞代谢中的异常作用的基本机制。具体的目的是（1）研究p53-Gamt-receatine途径在癌细胞中能量代谢中p53-GAMT-receatine途径的替代作用的潜在机制；（2）定义该途径在调节癌细胞中调节DNA损伤反应的作用（细胞命运决定；细胞命运或细胞死亡或存活）；（3）使用小鼠敲除方法确定GAMT在代谢和DNA损伤应力反应中的功能。我们对p53-> gamt-receatine途径的发现代表了细胞应激反应与肌酸合成和粮农组织的代谢过程之间的新联系，这对理解选择性的营养适应性以及这可能如何影响癌症的发育和对常规疗法的反应产生影响。拟议的研究与癌症生物学高度相关，因为它们将揭示代谢的变化如何影响癌症，以及这种新发现的途径如何成为肿瘤发生/致癌作用的关键因素。