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

描述（由申请人提供）：前列腺癌是一个重大的健康问题，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开发一种安全有效的前列腺癌预防策略。通过对前列腺癌免疫能力小鼠模型的研究，我们发现饮食剂withaferin-A （WA）能显著诱导自然杀伤细胞（NK）的激活。这种膳食剂叫withaferin-A，是一种无毒的、生物活性的化合物，提取自Withania somnifera植物，是亚洲和非洲广泛用于增强免疫系统的传统药物。然而，膳食剂WA对免疫细胞功能激活的调节机制在很大程度上仍然未知。根据我们的初步观察，我们假设膳食剂WA可以增强NK细胞的功能，从而抑制前列腺癌细胞的生长。我们假设的基本原理是基于WA的初步体外研究和流行病学研究，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细胞在小鼠前列腺转基因腺癌（TRAMP）中监测原发肿瘤提供了遗传学证据，这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对NK细胞的功能激活机制；2)探讨wa诱导NK细胞杀伤肿瘤的作用机制。本应用程序的总体目标是利用前列腺癌作为疾病模型系统地探讨这些问题。我们发现，膳食剂WA能够增强NK细胞的功能活性。这个项目将会提供一个具有高度影响力的新范例

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.