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饮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转导，从而抑制AKT的激活。我们最近发现了一个新的原癌基因，它激活了Notch-mTOR-AKT信号通路。此外，我们还从印度药用植物Aegle Marmelos中鉴定出一种新的化合物--蜜瓜。在初步研究中，我们已经确定蜜瓜蛋白通过肿瘤坏死因子介导的途径抑制结肠癌细胞在培养和移植瘤中的生长。我们还发现姜黄素和蜜瓜蛋白都能调节microRNA的表达。基于这些观察，我们提出了三个具体目标。在目标1中，我们将确定姜黄素和蜜蜜素在AOM/DSS诱导的小鼠结肠癌模型中预防肠道和结肠肿瘤形成的效果。在这里，我们将在引发炎症的小鼠身上进行一系列单一和联合治疗研究，并确定联合治疗是否在抑制结肠炎诱导的癌症方面更有效。在目标2中，我们将确定姜黄素和蜜蜜素介导的抑制RBM3的机制。在这里，我们确定了RBM3启动子中受两种化合物作用调节的区域。此外，我们还将确定化合物在RBM3过表达条件下对结肠癌生长和血管生成的影响。在目标3中，我们建议通过使用特定的抑制剂调节这两个化合物的表达来确定Notch-mTOR-Akt途径是否影响这两个化合物的活性。此外，我们还将确定影响这一途径的特定microRNAs对这两种化合物活性的作用。该项目完成后，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药物的临床试验。与公共健康相关：癌症是美国主要的死亡原因。了解正常细胞如何发展为癌症将有助于我们为这种可怕的疾病开发新的治疗方法。我们已经确定了一种原癌基因RBM3，它在癌细胞中的表达增加。过量表达RBM3蛋白会导致正常细胞转化为癌细胞。我们还从印度草本植物Aegle Marmelos中鉴定出一种新的化合物。我们已经在初步研究中确定该化合物与姜黄素具有协同抑制结肠癌生长的作用。我们目前的提案涉及确定姜黄素和蜜蜜素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理解肿瘤发生过程，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.