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

通过膳食产品调节 NK 细胞活性预防前列腺癌

• 批准号: 8354831
• 负责人: Dev Karan
• 金额: $ 19.71万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354831
• 关键词: Activated Natural Killer Cell; Adenocarcinoma; Africa; Asia; Biological Models; Cancer Etiology; Cancer Model; Cell physiology; Cells; Cessation of life; Dendritic Cells; Diet; Disease model; Epidemiologic Studies; Event; Figs - dietary; Future; Genes; Genetic; Goals; Growth; Health; Immune; Immune Cell Activation; Immune system; In Vitro; Interferons; Interleukin-12; Knockout Mice; Literature; Macrophage Activation; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Modeling; Molecular; Mus; NK Cell Activation; Natural Killer Cells; Plants; Prevention; Primary Neoplasm; Property; Prostate; Regulation; Research Project Grants; Role; Screening procedure; Second Primary Cancers; Staining method; Stains; TNF gene; Testing; Traditional Medicine; Transgenic Organisms; United States; Withania somnifera; Work; anticancer activity; base; cancer cell; cell killing; cytokine; design; granzyme B; in vivo; in vivo Model; innovation; macrophage; men; mouse model; novel; perforin; prevent; prostate cancer prevention; tumor

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. PUBLIC HEALTH RELEVANCE: This project is designed to characterize the significance of a dietary agent (withaferin-A) in regulating the anti- cancer activity of NK cells for prostate cance prevention. The mechanistic studies will examine the role of cytokines necessary for NK cells activity, and targeted molecules on NK cells engaged in tumoricidal activity using prostate cancer as a model system following withaferin-A treatment.

描述（由申请人提供）：前列腺癌是一个严重的健康问题，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。在使用免疫活性小鼠前列腺癌模型筛选膳食剂刺激免疫细胞功能的活性时，我们观察到膳食剂withaferin-A（WA）显著诱导自然杀伤（NK）细胞的活化。膳食剂，withaferin-A是一种无毒的生物活性化合物，来自植物睡茄，是在亚洲和非洲广泛使用的传统药物，以增强免疫系统。然而，通过膳食剂WA调节免疫细胞的功能活化的机制在很大程度上仍然未知。基于我们的初步观察，我们假设饮食剂WA增强NK细胞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WA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。最近的研究提供了在TRAMP（小鼠前列腺转基因腺癌）中通过NK细胞监测原发性肿瘤的遗传学证据，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对NK细胞功能性激活的机制; 2）表征WA诱导NK细胞杀肿瘤活性的机制。本申请的总体目标是使用前列腺癌作为疾病模型系统地探讨这些问题。我们已经发现，饮食剂WA能够增强NK细胞的功能活性。该项目将提供一个新的范例，在 鉴于文献中关于饮食剂如WA对前列腺癌模型中NK细胞的杀肿瘤活性的影响的信息很少，因此，本发明的方法在前列腺癌预防领域中是有效的。这些研究的成功完成将为未来使用WA刺激NK免疫细胞的抗癌特性以预防或延迟前列腺癌的转化应用提供理论基础。 公共卫生相关性：该项目旨在表征膳食剂（醉茄素-A）在调节NK细胞的抗癌活性以预防前列腺癌中的重要性。机制研究将使用前列腺癌作为withaferin-A治疗后的模型系统，检查NK细胞活性所需的细胞因子的作用，以及NK细胞上参与杀肿瘤活性的靶向分子。