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

描述（由申请人提供）：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。该研究项目的长期目标是制定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膳食制剂刺激免疫细胞功能的活性时，我们观察到膳食制剂withaferin-A (WA) 显着诱导自然杀伤 (NK) 细胞的激活。减肥剂睡茄素-A 是一种从睡茄植物中提取的无毒生物活性化合物，是在亚洲和非洲广泛使用的增强免疫系统的传统药物。然而，饮食剂 WA 调节免疫细胞功能激活的机制仍然很大程度上未知。根据我们的初步观察，我们假设饮食剂 WA 增强 NK 细胞功能，从而抑制前列腺癌细胞的生长。我们的假设的基本原理是基于西澳的初步体外研究和流行病学研究，表明膳食产品有助于维持健康的免疫系统。最近的研究为 TRAMP（小鼠前列腺转基因腺癌​​）中的 NK 细胞监测原发性肿瘤提供了遗传证据，TRAMP 是一种有用的前列腺癌模型。为了检验我们的假设，我们提出以下具体目标：1）确定WA激活NK细胞功能的机制； 2) 表征 WA 诱导 NK 细胞杀伤肿瘤活性的机制。本申请的总体目标是使用前列腺癌作为疾病模型来系统地探讨这些问题。我们发现膳食剂WA能够增强NK细胞的功能活性。该项目将提供一种在该领域具有重大影响的新颖范例 鉴于文献中缺乏有关膳食制剂（例如 WA）对前列腺癌模型中 NK 细胞杀肿瘤活性的影响的信息，因此该领域的研究成为前列腺癌预防领域的研究热点。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转化应用提供理论依据。

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.