Dietary methionine and cancer

营养可获得性(即饮食)可以影响新陈代谢途径，并决定癌症的需要量 细胞新陈代谢的程度与肿瘤中重新编程的代谢基因一样大。 我们和其他人之前的工作表明：1)蛋氨酸的可利用性影响一个碳循环 通量、DNA和组蛋白甲基化，因此表观遗传编程，2。日粮蛋氨酸限制 促进代谢健康，延长昆虫和哺乳动物的寿命，这两种抗癌表型， 3.)肿瘤中影响蛋氨酸代谢的基因的缺失使它们变得易感。 然而，这种饮食因素(以及一般的饮食)如何影响癌症预后在很大程度上是个问题。 未知。我们的初步数据显示，限制蛋氨酸可以延缓结直肠肿瘤的生长 癌症患者来源的异种移植(CRC PDX)模型和致敏基因工程小鼠 肉瘤模型以放射治疗为主。这些发现促使我们提议进行一项调查，以确定 这些表型背后的机制。我们将考虑以下目标。在目标1中，我们寻求 确定蛋氨酸限制敏感性的分子决定因素。我们将采用新陈代谢组学 使用我们实验室开发的代谢物分析平台和通量分析方法 目的：研究蛋氨酸限制对癌细胞代谢的影响。我们会 接下来，研究蛋氨酸代谢在肿瘤生长中的表观遗传学作用。结果将是 确定通过饮食蛋氨酸调节的代谢和表观遗传适应 新陈代谢。在目标2中，我们将确定肉瘤对蛋氨酸限制具有抗药性的原因，但 以协同的方式对膳食蛋氨酸限制和辐射作出反应。结果将定义 为了抵抗饮食操纵而发生的代谢和表观遗传机制 蛋氨酸代谢，但会导致饮食蛋氨酸限制和辐射的协同作用。在……里面 目的3，我们将确定蛋氨酸在甲硫腺苷中的作用。 磷酸化酶(MTAP)缺失的癌症。MTAP是蛋氨酸回收所必需的一种酶 PATH和最近的研究表明，MTAP中的缺失赋予了对 甲基化反应。结果，使用MTAP、膳食蛋氨酸和蛋氨酸代谢作为 模型系统将描述日粮蛋氨酸和MTAP之间的代谢相互作用 缺失并导致对遗传和环境之间相互作用的新理解， 特别是饮食和营养在调节癌症预后方面的作用。

Nutrient availability (i.e. diet) can affect metabolic pathways and determine the requirements of cancer cell metabolism to as large a degree as the metabolic genes that are reprogrammed in tumors. Previous work from us and others has shown that 1.) methionine availability affects one carbon cycle flux, DNA and histone methylation and thus epigenetic programming, 2.) dietary methionine restriction promotes metabolic health and extends insect and mammalian lifespan, two anti-cancer phenotypes, 3.) deletions of genes that affect methionine metabolism in tumors render them susceptible. Nevertheless, how this dietary factor (and diet in general) can influence cancer outcome is largely unknown. Our preliminary data shows that methionine restriction delays tumor growth in colorectal cancer patient derived xenograft (CRC PDX) models and sensitizes a genetically engineered mouse sarcoma model to radiation. These findings led us to propose an investigation to define the mechanisms underlying these phenotypes. We will consider the following aims. In aim 1 we seek to identify molecular determinants of sensitivity to methionine restriction. We will employ a metabolomics approach using a metabolite profiling platform and flux analysis method our laboratory has developed to investigate the metabolic changes in cancer cells that are induced by methionine restriction. We will next investigate the epigenetic role that methionine metabolism in tumor growth. The outcome will determine the metabolic and epigenetic adaptations that are modulated through dietary methionine metabolism. In aim 2, we will determine why the sarcomas are resistant to methionine restriction but respond to dietary methionine restriction and radiation in a synergistic manner. The outcome will define the metabolic and epigenetic mechanisms that occur in order to resist dietary manipulation of methionine metabolism but leads to a synergy effect of dietary methionine restriction and radiation. In aim 3, we will determine the role of methionine availability from diet in methylthioadenosine phosphorylase (MTAP)-deleted cancers. MTAP is an enzyme essential for the methionine salvage pathway and recent studies have shown that deletions in MTAP confer additional dependencies on methylation reactions. The outcome, using MTAP, dietary methionine, and methionine metabolism as a model system will characterize the metabolic interaction between dietary methionine and MTAP deletion and lead to a newfound understanding of the interaction between genetics and environment, particularly diet and nutrition in mediating cancer outcome.