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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：
8447577
负责人：
SAM W LEE
金额：
$ 31.81万
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/8447577
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(申请人提供)：癌细胞糖酵解增强并表现出较低的氧气消耗，表明转变为糖酵解以产生能量，从而促进被称为Warburg效应的新陈代谢变化，这几乎是所有癌症的特征。在我们对癌细胞新陈代谢的理解中，许多谜团仍未解开。最近的发现表明，抑癌基因P53具有更广泛的细胞功能，如调节葡萄糖代谢和线粒体呼吸。我们发现GAMT/乙酸胍甲基转移酶是参与肌酸合成代谢的一种新的p53靶基因，也是肿瘤细胞对DNA损伤和营养胁迫适应性反应的关键下游效应因子。我们揭示了GAMT参与了P53依赖的细胞凋亡对DNA损伤/基因毒性应激的响应，并证明了GAMT通路在营养胁迫下的ATP动态平衡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诱导的脂肪酸氧化(FAO)，从而促进了当葡萄糖缺乏时，这一途径作为替代的ATP生成能源的使用。这一应用的主要目的是了解P53-GAMT-肌酸通路在DNA损伤介导的致癌过程中以及在癌细胞代谢中的不寻常作用的潜在机制。其具体目的是(1)研究P53-GAMT-肌酸途径在癌细胞能量代谢中替代作用的潜在机制(S)；(2)确定该途径在调节癌细胞DNA损伤反应(决定细胞命运；细胞死亡或存活)中的作用；以及(3)利用小鼠基因敲除方法确定GAMT在代谢和DNA损伤应激反应中的功能。我们对P53-GAMT-肌酸途径的发现代表了细胞应激反应与肌酸合成代谢过程和粮农组织之间的新联系，为理解选择性营养适应以及这可能如何影响癌症的发展和对传统疗法的反应提供了启示。拟议的研究与癌症生物学高度相关，因为它们将揭示代谢变化如何影响癌症，以及这一新发现的途径如何成为肿瘤发生/癌症发生的关键因素。