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New Paradigm of Targeting COX-Catalyzed Free Radical Peroxidation in Colon Cancer

结肠癌中靶向 COX 催化的自由基过氧化的新范例

基本信息

批准号：
9022113
负责人：
Ang Guo
金额：
$ 43.5万
依托单位：
NORTH DAKOTA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-16 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9022113
关键词：
Accounting Address Apoptosis Apoptotic Arachidonic Acids Biological Assay Biology Cancer Cell Growth Cancer Etiology Cancer Patient Caring Cell Cycle Cell Proliferation Cell Survival Cells Cessation of life Colon Carcinoma Comet Assay Data Diet Dietary Intervention Disease Down-Regulation Effectiveness Enzymes FDA approved Fatty Acids Fluorescein-5-isothiocyanate Fluorouracil Free Radicals Growth HCT116 Cells HT29 Cells Health Human Hydroxyl Radical In Vitro Individual Inflammation Inflammatory Linolenic Acids Lipid Peroxidation Malignant Neoplasms Mammalian Cell Mediating Molecular North Dakota Omega-3 Fatty Acids Outcome Pathway interactions Pharmaceutical Preparations Polyunsaturated Fatty Acids Positioning Attribute Pre-Clinical Model Prostaglandin-Endoperoxide Synthase Proteins Recording of previous events Regimen Reporting Research Research Training Resources Role Second Primary Cancers Series Small Interfering RNA Staining method Stains Students TP53 gene Testing Therapeutic Therapeutic Intervention Time Transfection United States Universities annexin A5 base cancer cell cancer therapy colon cancer cell line cyclooxygenase 2 desaturase experience improved in vivo knock-down multidisciplinary peroxidation public health relevance response small hairpin RNA student training targeted treatment translational study tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Colon cancer remains a significant health concern as the third most prevalent cancer and the second leading cause of cancer deaths in the United States. Research suggests that ω-6 fatty acids are implicated in cancer due to the formation of deleterious metabolites from cyclooxygenase (COX)- catalyzed peroxidation. In contrast, ω-3 fatty acid-based dietary care has been applied in colon cancer treatment along with a variety of therapeutic approaches. Increasing evidence indicates that dihomo-- linolenic acid (DGLA) may represent an exceptional ω-6 that possesses beneficial bioactivities similar to ω-3s. However, the molecular mechanisms by which ω-6s can influence human health are still unclear. Our preliminary data has shown for the first time that, via COX-catalyzed peroxidation, DGLA produces exclusive free radicals that inhibit colon cancer cell growth, while its downstream product arachidonic acid (the conversion mediated by 5-desaturase) produces endoperoxide-derived free radicals that may stimulate cancer cell growth. We hypothesize that (1) the distinct free radical byproducts formed from COX-catalyzed peroxidation of arachidonic acid vs. DGLA account for their opposing bioactivities, and (2) down-regulation of 5-desaturase can inhibit colon cancer cell growth and enhance cancer therapy by limiting the conversion of DGLA to arachidonic acid, activating DGLA mediated pro-apoptotic and anti-proliferative pathways. Two specific aims will be pursued: (AIM-1) determine the role in colon cancer cell growth of the distinct arachidonic acid and DGLA free radical byproducts formed from COX-catalyzed peroxidation. We will test the hypothesis that the distinct free radical byproducts of arachidonic acid and DGLA are growth stimulatory and inhibitory, respectively, to colon cancer cells (HCA-7, HT-29, and HCT-116, with 3 different COX-2 and p53 statuses). These byproducts will be studied for their individual and combined effects on the expression of key proteins involved in the cell cycle and the apoptotic response; and (AIM-2) determine whether down-regulation of 5-desaturase enhances the formation of DGLA free radical byproducts during COX-catalyzed peroxidation, leading to inhibition of colon cancer growth and enhanced responses to chemo- and/or targeted therapeutic drugs in vitro and in vivo. We will use in vitro (three colon cancer cell lines and their 5-desaturase knockdown counterparts) and in vivo (xenograft tumors manipulated with 5- desaturase shRNA) strategies to test the hypothesis that down-regulation of 5-desaturase will intensify DGLA peroxidation catalyzed by COX-2 (high and readily inducible in cancer), enhance the inhibition of growth, and improve the efficacy of chemo- and/or targeted therapy. Our long term objective is to develop a strategy to modify cellular ω-6 conversion and COX-catalyzed free radical peroxidation for use in dietary regimens to optimize cancer therapies in colon cancer treatment.

描述（由申请人提供）：结肠癌仍然是美国第三大流行癌症和第二大癌症死亡原因的重要健康问题。研究表明，ω-6脂肪酸与癌症有关，这是由于环氧合酶（考克斯）催化的过氧化反应形成有害代谢物。相比之下，基于ω-3脂肪酸的饮食护理已经与各种治疗方法一起沿着应用于结肠癌治疗。越来越多的证据表明，二高-亚麻酸（DGLA）可能是一种特殊的ω-6，具有类似于ω-3的有益生物活性。然而，ω-6s影响人类健康的分子机制仍不清楚。我们的初步数据首次表明，通过COX催化的过氧化，DGLA产生抑制结肠癌细胞生长的专属自由基，而其下游产物花生四烯酸（由β 5-去饱和酶介导的转化）产生可能刺激癌细胞生长的内过氧化物衍生的自由基。我们假设：（1）花生四烯酸与DGLA的COX-催化过氧化反应形成的不同自由基副产物导致了它们相反的生物活性，以及（2）β 5-去饱和酶的下调可以通过限制DGLA转化为花生四烯酸、激活DGLA介导的促凋亡和抗增殖途径来抑制结肠癌细胞生长并增强癌症治疗。将追求两个具体目标：（AIM-1）确定不同的花生四烯酸和DGLA自由基副产物形成的COX-催化的过氧化作用在结肠癌细胞生长中的作用。我们将检验花生四烯酸和DGLA的不同自由基副产物分别对结肠癌细胞（HCA-7、HT-29和HCT-116，具有3种不同的考克斯-2和p53状态）具有生长刺激性和抑制性的假设。将研究这些副产物对参与细胞周期和凋亡反应的关键蛋白质表达的单独和联合作用;和（AIM-2）确定在COX-催化的过氧化过程中β 5-去饱和酶的下调是否增强DGLA自由基副产物的形成，导致结肠癌生长的抑制和体外和体内对化疗和/或靶向治疗药物的增强反应。我们将使用体外（三种结肠癌细胞系及其β 5-去饱和酶敲低对应物）和体内（用β 5-去饱和酶shRNA操纵的异种移植肿瘤）策略来测试以下假设：β 5-去饱和酶的下调将增强由考克斯-2（在癌症中高且容易诱导）催化的DGLA过氧化，增强生长抑制，并提高化疗和/或靶向治疗的功效。我们的长期目标是开发一种策略来改变细胞ω-6转化和COX催化的自由基过氧化作用，用于饮食方案，以优化结肠癌治疗中的癌症疗法。