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），其消费量随着时间的推移而增加。除了心血管益处之外，据报道EPA以诱导许多癌细胞系凋亡的形式具有化学预防作用，但其机制尚不清楚。我们已经确定了环氧合酶（考克斯）-2-衍生代谢产物的EPA衍生的前列腺素D3（PGD 3）在免疫细胞（巨噬细胞和T细胞）的形式？12-PGJ 3（最主要和稳定的代谢产物），和15-脱氧-？12-14-PGJ 3（15 d-PGJ 3），统称为环戊烯酮PG（CyPG）。根据我们最近发表的初步数据，我们认为CyPG在nM浓度下靶向癌症干细胞凋亡。为了说明这种新的和以前未描述的抗癌特性，我们利用了一个完善的慢性髓性白血病（CML）模型，涉及白血病干细胞（LSC）。LSC位于发育层次的顶点，并促进大量肿瘤细胞的持续扩增，导致疾病复发。我们的研究是基于这样的假设，即来自EPA的CyPG通过激活CyPG-受体-p53信号传导轴选择性地靶向LSC以进行凋亡。将在CML模型中测试源自EPA的生物活性组分的抗白血病作用，其中将经转导以表达人融合蛋白BCR-Abl的原代鼠造血干细胞（HSC）移植到喂食高EPA饮食以模拟人类消耗的小鼠中。鉴于这是第一次研究，我们将研究饮食EPA的代谢？12-PGJ 3和15-脱氧-？12，14-PGJ 3体内测定，以确认目标1中CyPG的内源性产生量足够（nM范围）。在目标2中，我们将测试EPA衍生的内源性PGJ 3对LSC消融的作用，并说明考克斯抑制剂（常用的NSAID）在减弱EPA作用中的作用。在目的3，我们将阐明p53的激活途径，通过结合？12-PGJ 3与LSC中表达的CyPG（DP）受体的结合。我们的长期目标是了解生物活性代谢物的健康益处？3脂肪酸，并在CML患者中翻译这些发现。

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.