Effect of Omega-3 Fatty Acids on Cancer Stem Cells

描述（由申请人提供）：二十碳五烯酸（EPA）是一种omega （?）-3多不饱和脂肪酸（PUFA），其摄入量随着时间的推移而增加。除了心血管方面的益处外，据报道EPA还具有诱导许多癌细胞凋亡的化学预防作用，但其机制尚不清楚。我们已经在免疫细胞（巨噬细胞和t细胞）中发现了环氧化酶(COX)-2衍生的epa衍生的前列腺素D3 （PGD3）代谢物。12-PGJ3（最主要和最稳定的代谢物）和15-deoxy-？12-14-PGJ3 (15d-PGJ3)，统称环戊烯酮pg （CyPGs）。根据我们最近发表的和初步的数据，我们认为CyPGs在nM浓度下靶向肿瘤干细胞凋亡。为了说明这种新颖和以前未描述过的抗癌特性，我们利用了一个成熟的涉及白血病干细胞（LSCs）的慢性髓性白血病（CML）模型。LSCs位于发育层次的顶端，促进大块肿瘤细胞的持续扩张，导致疾病复发。我们的研究基于EPA衍生的cypg通过激活cypg受体-p53信号轴选择性靶向LSCs导致细胞凋亡的假设。来自EPA的生物活性成分的抗白血病作用将在CML模型中进行测试，在CML模型中，原代小鼠造血干细胞（hsc）被转导表达人类融合蛋白BCR-Abl，将被移植到喂养高EPA饮食的小鼠中，以模仿人类的消费。鉴于这是同类研究中的第一次，我们将检查膳食EPA的代谢。12-PGJ3和15-脱氧- ？12,14- pgj3在体内确认内源性产生足够量的CyPGs （nM范围）。在Aim 2中，我们将测试EPA来源的内源性PGJ3对LSCs消融的影响，并解决COX抑制剂（常用的非甾体抗炎药）在减弱EPA作用中的作用。在Aim 3中，我们将通过结合？12- PGJ3 - CyPG （DP）受体在LSCs中的表达。我们的长期目标是了解生物活性代谢产物对健康的益处？-3脂肪酸并将这些发现转化为CML患者

DESCRIPTION (provided by applicant): Eicosapentaenoic acid (EPA) is an omega (?)-3 polyunsaturated fatty acid (PUFA) whose consumption has increased over time. Apart from cardiovascular benefits, EPA is reported to have chemo preventive effects in form of induction of apoptosis of many cancer cell lines, but the mechanisms are unclear. We have identified cyclooxygenase (COX)-2-derived metabolites of EPA-derived prostaglandin D3 (PGD3) in immune cells (macrophages and T-cells) in the form of ?12-PGJ3 (most predominant and stable metabolite), and 15-deoxy-?12-14-PGJ3 (15d-PGJ3), collectively referred to as cyclopentenone PGs (CyPGs). Based on our recently published and preliminary data, we believe that CyPGs target cancer stem cells for apoptosis at nM concentrations. To illustrate this novel and previously undescribed anticancer property, we have utilized a well-established model of chronic myelogenous leukemia (CML) that involves leukemia stem cells (LSCs). LSCs reside at the apex of a developmental hierarchy and facilitate the continued expansion of bulk tumor cells leading to relapse of the disease. Our studies are based on the hypothesis that CyPGs derived from EPA selectively target LSCs via the activation of CyPG-receptor-p53 signaling axis for apoptosis. The anti-leukemic role of bioactive components derived from EPA will be tested in the CML model, where primary murine hematopoietic stem cells (HSCs) transduced to express the human fusion protein, BCR-Abl, will be transplanted into mice fed a high EPA diet to mimic human consumption. Given that this is a first study of its kind, we will examine the metabolism of dietary EPA to ?12-PGJ3 and 15-deoxy- ?12,14-PGJ3 in-vivo to confirm endogenous production of CyPGs in sufficient amounts (nM range) in Aim 1. In Aim 2, we will test the effects of EPA-derived endogenous PGJ3 on the ablation of LSCs and address the role of COX inhibitors (commonly used NSAIDs) in the blunting of the effects of EPA. In Aim 3, we will elucidate pathways of activation of p53 via the binding of ?12- PGJ3 to CyPG (DP) receptors expressed in LSCs. Our long-term goal is to understand the health benefits of bioactive metabolites of ?-3 fatty acids and translate these findings in CML patients.