Dietary Prevention of Cancer

描述（由申请人提供）：该项目的主要目标是了解纯化的膳食化合物预防肿瘤生长和发展的机制。在过去的周期中，我们已经确定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活化。我们最近发现了一种新的原癌基因，它激活Notch-mTOR-AKT信号通路。此外，我们已经确定了一个新的化合物marmelin从印度药用植物Aegle marmelos。在初步研究中，我们已经确定，marmelin抑制结肠癌细胞的生长，在文化和肿瘤异种移植物通过肿瘤坏死因子介导的途径。我们还发现，姜黄素和marmelin都调节microRNA的表达。根据这些观察，我们提出了三个具体目标。在目标1中，我们将确定姜黄素和马默林的组合在AOM/DSS诱导的小鼠结肠癌模型中预防肠和结肠肿瘤发生的功效。在这里，我们将在已经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。在目标2中，我们将确定姜黄素和marmelin介导的RBM 3抑制的机制。在这里，我们确定了区域的RBM 3启动子，这是由两种化合物的行动。此外，我们将确定在RBM 3过表达的条件下化合物对结肠肿瘤生长和血管生成的影响。在目标3中，我们提出确定Notch-mTOR-Akt通路是否通过使用特异性抑制剂调节其表达来影响两种化合物的活性。此外，我们将确定影响这一途径的特定microRNA对两种化合物活性的作用。在项目完成后，我们将有有利的，令人信服的证据，启动临床试验的两种化合物作为化学预防剂。公共卫生相关性：癌症是美国的主要死亡原因。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。我们已经确定了一个原癌基因，RBM 3，其表达在癌细胞中增加。过度表达RBM 3蛋白会导致正常细胞转化为癌细胞。我们还从印度草药Aegle marmelos中鉴定出一种新化合物。我们已经在初步研究中确定，这种化合物与姜黄素协同作用，以抑制结肠癌的生长。我们目前的建议涉及确定姜黄素和马默林这两种化合物抑制结肠癌发展的机制。.我们希望这项工作将有助于更好地了解肿瘤发生过程，并确定新的方法来阻止或减缓肿瘤发生。

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.