DIET,APOPTOSIS AND COLON CARCINOGENESIS

饮食、细胞凋亡和结肠癌发生

• 批准号: 6266806
• 负责人: JOANNE R LUPTON
• 金额: $ 32.44万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6266806
• 关键词: apoptosis; butyrates; cardiolipins; cell differentiation; cell proliferation; chemical carcinogen; chemical carcinogenesis; colon neoplasms; cyclin dependent kinase; cyclins; dietary lipid; dietary supplements; enzyme activity; enzyme inhibitors; free radical oxygen; immunocytochemistry; laboratory rat; marine animal oil; mitochondria; nutrition aspect of cancer; nutrition related tag; prostaglandin endoperoxide synthase; vegetable oils

DESCRIPTION: Others and we have shown that fish oil vs corn oil, is protective against experimentally-induced colon cancer. Recently we reported that this protective effect is due to a higher steady state level of apoptosis with fish oil supplementation. In addition, we show a synergistic protective effect of the combination of fish oil and pectin (a highly fermentable fiber) on both tumor incidence and enhancement of spontaneous apoptosis. We now show data that the combination of fish oil and pectin also enhances targeted apoptosis within the first 12 hours after administration of the carcinogen azoxymethane (AOM). The overall goal of this proposal is to understand, at a mechanistic level, how fish oil, high in n-3 fatty acids, induces apoptosis in colonocytes and thus protects against experimentally-induced colon tumorigenesis. A secondary goal is to determine how supplementing fish oil-containing diets with pectin compared to cellulose synergistically enhances the protective effect of fish oil. Hypotheses: The observed enhancement of apoptosis with fish oil supplementation is due to (1) down regulation of Cox-2 expression providing a permissive environment for butyrate-induced apoptosis; and/or (2) alterations in mitochondrial function which are permissive for butyrate-induced apoptosis. To test these hypotheses we have three specific aims: 1. Determine in vivo expression of Cox-2, apoptosis, p21waf1/CipI p27kip1, Cyclin Dl, cell proliferation and differentiation as a function of dietary lipid, butyrate, and carcinogen administration, during the stage of promotion. Using a 3 x 2 x 2 factorial design (fish oil, fish oil ethyl esters, or corn oil supplementation; plus or minus butyrate; saline or AOM), we will use quantitative immunohistochemistry on serial sections of rat colon to detect patterns of expression of Cox-2, apoptosis, p21 WAFI/CIPI and Cyclin Dl; and p27Kip1 differentiation, and apoptosis in the same cells. 2. Determine in vivo expression of the same markers as in specific aim #1, as a function of dietary lipid, butyrate, and AOM, but during the initiation stage of colon cancer. 3. Determine in an ex vivo system if fish oil alters mitochondrial function thus creating a permissive environment for butyrate-induced apoptosis. Using a 3 x 2 factorial design (fish oil; fish oil ethyl esters or corn oil; saline or AOM), during the stage of promotion we will determine the effect on known indicators of mitochondrial function, reactive oxygen species, cardiolipin fatty acid composition and butyrate-induced apoptosis. An understanding of how diet affects colon tumor incidence has important consequences for the design of clinical trials and for future dietary recommendations.

描述：其他人，我们已经证明鱼油与玉米油具有保护性 针对实验诱导的结肠癌。最近我们报道了 保护作用是由于鱼的凋亡稳态水平较高 补充油。此外，我们还显示了一种协同的保护作用 鱼油和果胶（高度发酵纤维）的组合 肿瘤发生率和自发凋亡的增强。我们现在显示数据 鱼油和果胶的组合还增强了靶向凋亡 服用致癌甲甲烷（AOM）后的前12小时。 该提案的总体目标是在机械层面上了解 鱼油，高3-3脂肪酸，诱导结肠细胞的凋亡，从而诱导 预防实验诱导的结肠肿瘤发生。次要目标 是确定如何用果胶补充含鱼油的饮食 与纤维素相比，协同增强了鱼类的保护作用 油。假设：观察到的鱼油凋亡的增强 补充是由于（1）减少COX-2表达的调节 丁酸酯引起的凋亡的允许环境；和/或（2）变化 在线粒体功能中允许丁酸酯诱导的细胞凋亡。 为了检验这些假设，我们有三个特定的目的：1。确定体内 Cox-2，凋亡，P21WAF1/CIPI P27KIP1，细胞周期蛋白DL，细胞的表达 增殖和分化是饮食脂质，丁酸酯和 促进阶段的致癌物给药。使用3 x 2 x 2 阶乘设计（鱼油，鱼油乙酯或补充玉米油； 加上或减去丁酸酯；盐水或AOM），我们将使用定量 大鼠结肠串行切片的免疫组织化学检测模式 Cox-2，凋亡，p21 WAFI/CIPI和Cyclin DL的表达；和p27kip1 在同一细胞中的分化和凋亡。 2。确定体内 与特定目标＃1相同的标记的表达，作为饮食的函数 脂质，丁酸酯和AOM，但在结肠癌的启动阶段。 3。 在离体系统中确定鱼油是否会改变线粒体功能 为丁酸酯诱导的凋亡创造一个允许的环境。使用3 x 2 阶乘设计（鱼油；鱼油乙酯或玉米油；盐水或AOM）， 在晋升阶段，我们将确定对已知指标的影响 线粒体功能，活性氧，心磷脂脂肪酸 组成和丁酸诱导的凋亡。对饮食的理解 影响结肠肿瘤的发病率对设计有重要影响 临床试验和未来的饮食建议。