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

描述（由申请人提供）：癌细胞糖酵解增强，耗氧量降低，表明糖酵解产生能量的转变，从而促进了被称为Warburg效应的代谢变化，这是几乎所有癌症的特征。在我们对癌细胞代谢的理解中，还有许多未解之谜。最近的发现表明，肿瘤抑制因子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/guanidinoacetate methyltransferase，一种参与肌酸合成代谢的酶，是p53的一个新的靶基因，也是癌细胞DNA损伤和营养应激适应性反应的关键下游效应因子。我们发现GAMT参与了p53依赖性细胞凋亡对DNA损伤/基因毒性应激的反应，并证明了GAMT通路在营养胁迫下ATP稳态的调节中起重要作用。令人惊讶的是，我们还发现p53->GAMT上调DNA损伤应激或葡萄糖饥饿诱导的脂肪酸氧化（FAO），促进了在葡萄糖稀缺时将该途径作为替代的atp生成能量来源。本应用程序的主要目的是了解p53- gmt -肌酸途径在DNA损伤介导的致癌作用以及癌细胞代谢中的不寻常作用的潜在机制。具体目的是：(1)研究p53- gamt -肌酸途径在癌细胞能量代谢中的替代作用的潜在机制；(2)明确该通路在调节癌细胞DNA损伤反应（细胞命运决定、细胞死亡或存活）中的作用；(3)利用小鼠敲除法确定GAMT在代谢和DNA损伤应激反应中的功能。我们关于p53-> gamt -肌酸通路的发现代表了细胞应激反应与肌酸合成和FAO代谢过程之间的新联系，为理解选择性营养适应及其如何影响癌症发展和对常规疗法的反应提供了意义。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/致癌的关键因素。

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.