Modulation of NK cell activity by dietary product for prostate cancer prevention

描述(申请人提供)：前列腺癌是一个严重的健康问题，也是美国男性癌症死亡的第二大原因，估计每年有30,000人死亡。这项研究项目的长期目标是开发一种安全有效的前列腺癌预防策略。在使用前列腺癌免疫活性小鼠模型筛选饮食制剂刺激免疫细胞功能的活性时，我们观察到含有铁蛋白-A(Wa)的饮食制剂显著诱导自然杀伤(NK)细胞的激活。这种膳食剂是一种无毒的生物活性化合物，来自植物薇菜，是亚洲和非洲广泛使用的增强免疫系统的传统药物。然而，饮食制剂调节免疫细胞功能激活的机制(S)在很大程度上仍不清楚。根据我们的初步观察，我们假设饮食制剂WA增强了NK细胞的功能，以抑制前列腺癌细胞的生长。我们假设的基本原理是基于对西澳人的初步体外研究和流行病学研究，这些研究表明，饮食产品有助于维持健康的免疫系统。最近的研究为NK细胞在TRAMP(转基因小鼠前列腺癌)中监测原发肿瘤提供了遗传学证据，TRAMP是一种有用的前列腺癌模型。为了验证我们的假设，我们提出了以下具体目标：1)确定WA激活NK细胞的功能机制；2)表征WA诱导NK细胞杀瘤活性的机制。本应用程序的总体目标是以前列腺癌作为疾病模型，系统地探讨这些问题。我们发现膳食制剂Wa能够增强NK细胞的功能活性。该项目将提供一种新的范例，在 在前列腺癌预防领域，由于在前列腺癌模型中缺乏关于饮食制剂(如WA)对NK细胞杀瘤活性的影响的信息。这些研究的成功完成将为未来利用WA刺激NK免疫细胞的抗癌特性来预防或延缓前列腺癌的翻译应用提供理论基础。

DESCRIPTION (provided by applicant): Prostate cancer is a significant health problem and the second leading cause of cancer death among men in the United States with an estimated 30,000 deaths every year. The long-term goal of this research project is to develop a safe and effective strategy for prostate cancer prevention. While screening for the activity to stimulate immune cell function by dietary agents using an immune-competent mouse model for prostate cancer, we observed that the dietary agent withaferin-A (WA) significantly induced the activation of natural killer (NK) cells. The dietary agent, withaferin-A is a non-toxic, bioactive compound derived from the plant Withania somnifera, and is traditional medicine widely used in Asia and Africa to boost the immune system. However, the mechanism(s) regulating the functional activation of immune cells by the dietary agents WA remain largely unknown. Based on our preliminary observations, we hypothesize that the dietary agent WA augments NK cell function to inhibit the growth of prostate cancer cells. The rationale for our hypothesis is based on preliminary in vitro studies with WA and on epidemiologic studies indicating that dietary products help to maintain a healthy immune system. Recent studies provide genetic evidence for surveillance of primary tumors by NK cells in the TRAMP (transgenic adenocarcinoma of the mouse prostate), a useful model of prostate cancer. To test our hypothesis, we propose the following specific aims: 1) To determine the mechanism of functional activation of NK cells by WA; and 2) To characterize the mechanism of WA-induced tumoricidal activity by NK cells. The overall objective of this application is to systematically probe into these questions using prostat cancer as a disease model. We have found that the dietary agent WA is able to enhance the functional activity of NK cells. This project will provide a novel paradigm with high impact in the field of prostate cancer prevention given the paucity of information in the literature on the effec of dietary agents such as WA on the tumoricidal activity of NK cells in a prostate cancer model. Successful accomplishment of these studies will provide a rationale for future translational applications using WA to stimulate anticancer properties of NK immune cells for the prevention or delaying of prostate cancer.