Dietary Prevention of Cancer

描述（由申请人提供）：该项目的总体目标是了解纯化膳食化合物防止肿瘤生长和发展的机制。在过去的周期中，我们已经发现姜黄素通过其同源受体EGFR抑制表皮生长因子介导的信号传导，从而抑制AKT的激活。我们最近发现了一个新的原癌基因，它可以激活Notch-mTOR-AKT信号通路。此外，我们还从印度药用植物柑橘中鉴定出一种新的化合物柑橘素。在初步研究中，我们已经确定，在培养和肿瘤异种移植中，杏仁素通过tnf介导的途径抑制结肠癌细胞的生长。我们还发现姜黄素和杏仁素都能调节microRNA的表达。基于这些观察，我们提出了三个具体目标。在Aim 1中，我们将在AOM/ dss诱导的小鼠结肠癌模型中确定姜黄素和豆蔻素联合使用对肠道和结肠肿瘤发生的预防作用。在这里，我们将在引发炎症的小鼠中进行一系列单一和联合治疗研究，并确定该组合是否更有效地抑制结肠炎诱导的癌症。在Aim 2中，我们将确定姜黄素和橘子素介导的RBM3抑制的机制。在这里，我们确定了RBM3启动子中受这两种化合物作用调节的区域。此外，我们将在RBM3过表达的情况下确定化合物对结肠肿瘤生长和血管生成的影响。在Aim 3中，我们建议通过使用特异性抑制剂调节Notch-mTOR-Akt通路的表达来确定Notch-mTOR-Akt通路是否会影响这两种化合物的活性。此外，我们将确定影响这两种化合物活性途径的特定microrna的作用。项目完成后，我们将有有利的、令人信服的证据来启动这两种化合物作为化学预防剂的临床试验。公共卫生相关性：在美国，癌症是导致死亡的主要原因。了解正常细胞如何发展为癌症将有助于我们开发针对这种可怕疾病的新疗法。我们已经确定了一种原癌基因，RBM3，其表达在癌细胞中增加。过度表达RBM3蛋白会导致正常细胞转变为癌细胞。我们还从印度草药柑橘中鉴定出一种新的化合物。我们在初步研究中确定，这种化合物与姜黄素协同作用，抑制结肠癌的生长。我们目前的建议是确定姜黄素和橘子素这两种化合物抑制结肠癌发展的机制。我们期望这项工作将有助于更好地了解肿瘤发生过程，并找到阻止或减缓肿瘤发生的新方法。

DESCRIPTION (provided by applicant): The broad goal of the project is to understand the mechanisms by which purified dietary compounds prevent the growth and development of tumors. Suring the past cycle, we have identified that curcumin inhibits epidermal growth factor mediated signaling through its cognate receptor EGFR thereby inhibiting AKT activation. We have recently identified a novel protooncogene which activates the Notch-mTOR-AKT signaling pathway. In addition, we have identified a novel compound marmelin from the Indian Medicinal plant Aegle marmelos. In preliminary studies, we have determined that marmelin inhibits colon cancer cell growth in culture and in tumor xenografts through the TNF-mediated pathway. We have also identified that both curcumin and marmelin modulate microRNA expression. Based on these observations, we propose three specific aims. In Aim 1, we will determine the efficacy of a combination of curcumin and marmelin in preventing intestinal and colonic tumorigenesis in the AOM/DSS-induced mouse colon cancer model. Here, we will perform a series of single and combination treatment studies in mice that have initiated inflammation and determine whether the combination is more potent in inhibiting colitis induced cancers. In Aim 2, we will determine the mechanism of curcumin- and marmelin-mediated suppression of RBM3. Here, we identify the regions in the RBM3 promoter that is regulated by the actions of the two compounds. In addition, we will determine the effect of the compounds on colon tumor growth and angiogenesis under condition of RBM3 overexpression. In Aim 3, we propose to determine whether the Notch-mTOR-Akt pathway affects the activity of the two compounds by modulating their expression using specific inhibitors. In addition, we will determine the role of specific microRNAs that affect this pathway on the activity of the two compounds. Upon completion of the project, we will have favorable, compelling evidence for initiating clinical trials for the two compounds as chemopreventive agents. PUBLIC HEALTH RELEVANCE: Cancer is the leading cause of death in the United States. Understanding how the normal cell progresses to a cancer will aid in our developing novel therapies for this dreaded disease. We have identified a protooncogene, RBM3 whose expression is increased in cancer cells. Overexpressing RBM3 protein causes a normal cell to become transformed into a cancer cell. We have also identified a novel compound from the Indian herb Aegle marmelos. We have determined in preliminary studies that this compound synergizes with curcumin to inhibit colon cancer growth. Our current proposal deals with determining the mechanism by which the two compounds, curcumin and marmelin inhibit colon cancer from developing. . We expect that the work will lead to a better understanding of the tumorigenesis process and identify novel methods to stop or slow down tumorigenesis.