Effect of Omega-3 Fatty Acids on Cancer Stem Cells

Omega-3 脂肪酸对癌症干细胞的影响

• 批准号: 8511593
• 负责人: ROBERT Frank PAULSON
• 金额: $ 28.49万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511593
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Ablation; Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Arachidonic Acids; Area; Binding; Blood; Bone Marrow; Cancer cell line; Cardiovascular system; Cell Line; Cells; Chemopreventive Agent; Chimeric Proteins; Chronic Myeloid Leukemia; Complementary and alternative medicine; Consumption; Coxibs; Cyclooxygenase Inhibitors; Data; Development; Diet; Dinoprostone; Eicosapentaenoic Acid; Enzymes; Exhibits; Fatty Acids; G-Protein-Coupled Receptors; Gene Expression; Goals; Growth; Health Benefit; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immune; Induction of Apoptosis; Inflammatory; Inhibitory Concentration 50; Lead; Link; Lipids; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Marines; Membrane; Metabolic; Metabolism; Modeling; Monitor; Mus; Non-Steroidal Anti-Inflammatory Agents; Normal Cell; Omega-3 Fatty Acids; Oncogene Proteins; Pathway interactions; Patients; Phosphotransferases; Polyunsaturated Fatty Acids; Population; Preventive; Production; Property; Prostaglandin D2; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Publishing; Recurrent disease; Reporting; Role; Series; Signal Transduction; Simulate; Spleen; Splenomegaly; Stem cell transplant; T-Lymphocyte; Testing; Time; Transcriptional Activation; Translating; Transplantation; ataxia telangiectasia mutated protein; base; bcr-abl Fusion Proteins; bioactive food component; cancer cell; cancer stem cell; cyclooxygenase 2; cyclopentenone; feeding; in vivo; inhibitor/antagonist; interest; intraperitoneal; leukemia; leukemic stem cell; macrophage; neoplastic cell; novel; programs; prostaglandin E3; prostaglandin I3; prostaglandin R2 D-isomerase; receptor; receptor binding; research study; tumor; tumorigenesis

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.

描述(由申请人提供)：二十碳五烯酸(EPA)是一种欧米伽-3多不饱和脂肪酸(PUFA)，其消费量随着时间的推移而增加。据报道，除了对心血管有好处外，EPA还通过诱导许多癌细胞株的凋亡来发挥化疗预防作用，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)中鉴定了环氧合酶(COX)-2衍生的前列腺素D3(PGD3)的代谢物，其形式为12-PGJ3(最主要和稳定的代谢物)和15-脱氧-12-14-PGJ3(15d-PGJ3)，统称为环戊酮PGs(CyPGs)。根据我们最近发表的初步数据，我们认为CyPGs在NM浓度下靶向肿瘤干细胞进行凋亡。为了说明这一新的和以前未描述的抗癌特性，我们使用了一个涉及白血病干细胞(LSCs)的慢性粒细胞白血病(CML)模型。LSCs位于发育层级的顶端，促进肿瘤细胞的持续扩张，导致疾病复发。我们的研究是基于这样一种假设，即来自EPA的CyPG通过激活CyPG受体-P53信号轴来选择性地靶向LSCs进行细胞凋亡。从EPA中提取的生物活性成分的抗白血病作用将在CML模型中进行测试，在该模型中，转化为表达人类融合蛋白BCR-Abl的原代小鼠造血干细胞将被移植到喂食高EPA饮食的小鼠体内，以模拟人类的消费。鉴于这是此类研究的第一次，我们将检测饮食中EPA对12-PGJ3和15-脱氧-12，14-PGJ3的体内代谢，以确认在目标1中内源性产生足够量(NM范围)的CyPG。在目标2，我们将测试EPA衍生的内源性PGJ3对LSCs消融的影响，并讨论COX抑制剂(常用的非甾体抗炎药)在钝化EPA的影响中的作用。在目标3中，我们将阐明P53的激活途径是通过与LSC中表达的CyPG(DP)受体结合来实现的。我们的长期目标是了解β-3脂肪酸的生物活性代谢物对健康的益处，并将这些发现转化为CML患者。