Colonic Cytokinetics and Cell Signaling: Dietary Effects

结肠细胞动力学和细胞信号传导：饮食影响

• 批准号: 6872973
• 负责人: Robert Stephen Chapkin
• 金额: $ 27.35万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-23 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6872973
• 关键词: apoptosis; biological signal transduction; butyrates; cell component structure /function; cell line; cell membrane; colon; colon neoplasms; dietary lipid; gene expression; laboratory mouse; laboratory rat; mitochondria; nutrition aspect of cancer; nutrition related tag; omega 3 fatty acid; oncogenes; oxidative stress; unsaturated fatty acids

DESCRIPTION (provided by applicant): Among dietary factors, there are cogent data indicating a protective effect of n-3 polyunsaturated fatty acids (PUFA) e.g., eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), on colon cancer. In contrast, dietary lipids rich in n-6 PUFA, e.g., linoleic acid (18:2n-6) and arachidonic acid (20:4n-6), enhance the development of colon tumors. This is significant because the typical Western diet contains 10 to 20 times more n-6 than n-3 PUFA. Unfortunately, to date, a unifying mechanistic hypothesis addressing why n-3 PUFA selectively suppress colon cancer compared to n-6 PUFA (the major dietary form of PUFA in the U.S. diet) is lacking. We have recently shown that (i) the antitumorigenic effects of n-3 PUFA are in part the result of the coordinated upregulation of targeted apoptosis dudng the initiation phase of tumorigenesis and spontaneous apoptosis during tumor promotion; (ii) the effect is enhanced by butyrate; (iii) EPA and DHA induce compositional changes in mitochonddal membrane phospholipids which facilitate apoptosis; and (iv) n-3 PUFA suppress oncogenic Ras activation, a powerful antiapoptotic signal in the colon. Since the inhibition of apoptosis is now thought to be an integral component in the genesis of colorectal tumors, the overall goal of this proposal is to understand how n-3 PUFA promote apoptosis in colonocytes. Since n-3 PUFA are uniquely capable of altering cell membrane properties due to both the number and position of double bonds, we have hypothesized that n-3 PUFA alter colonocyte mitochondrial and plasma membrane composition and function, thereby creating a permissive environment for apoptosis. We propose to utilize a combination of experimental models (azoxymethane-injected rat, oxidatively stressed SOD2+/- mouse; normal and malignant transformed mouse and human colonocyte cell lines) in order to elucidate n-3 PUFA apoptogenic signaling in the colon. To test our hypothesis the following specific aims are proposed: Aim #1 will elucidate the mechanisms by which n-3 PUFA modulate intrinsic (mitochondria-mediated) cell death signaling; and Aim #2 will determine the mechanisms by which n-3 PUFA modulate extrinsic (non-mitochondrial) cell death signaling. At present, the molecular basis of the n-3 PUFA effects on colonocyte apoptosis is a complete black box. The proposed experiments represent the first attempt to provide an explanation of EPA and DHA action at the molecular level.

描述（由申请人提供）：在饮食因素中，有令人信服的数据表明n-3多不饱和脂肪酸（PUFA）的保护作用，例如，二十碳五烯酸（EPA; 20：5 n-3）和二十二碳六烯酸（DHA，22：6 n-3）对结肠癌的作用。相反，富含n-6 PUFA的膳食脂质，例如，亚油酸（18：2n-6）和花生四烯酸（20：4 n-6），促进结肠肿瘤的发展。这是很重要的，因为典型的西方饮食中含有的n-6比n-3多不饱和脂肪酸多10到20倍。不幸的是，到目前为止，还缺乏一个统一的机制假说来解释为什么n-3 PUFA与n-6 PUFA（美国饮食中PUFA的主要饮食形式）相比选择性地抑制结肠癌。我们最近的研究表明：（i）n-3 PUFA的抗肿瘤作用部分是由于在肿瘤发生的起始阶段协同上调靶向细胞凋亡和肿瘤促进过程中的自发性细胞凋亡;（ii）丁酸盐增强了这种作用;（iii）EPA和DHA诱导线粒体膜磷脂的组成变化，从而促进细胞凋亡;和（iv）n-3 PUFA抑制致癌Ras活化，这是结肠中的强有力的抗凋亡信号。由于细胞凋亡的抑制现在被认为是结直肠肿瘤发生中不可或缺的组成部分，因此本提案的总体目标是了解n-3 PUFA如何促进结肠细胞凋亡。由于n-3多不饱和脂肪酸是唯一能够改变细胞膜的性质，由于双键的数量和位置，我们假设，n-3多不饱和脂肪酸改变结肠细胞线粒体和质膜的组成和功能，从而创造一个允许的环境凋亡。我们建议利用实验模型（氧化偶氮甲烷注射大鼠，氧化应激SOD 2 +/-小鼠，正常和恶性转化的小鼠和人类结肠细胞系）的组合，以阐明n-3 PUFA在结肠中的致癌信号。为了验证我们的假设，提出了以下具体目标：目标1将阐明n-3 PUFA调节内在（线粒体介导）细胞死亡信号的机制;目标2将确定n-3 PUFA调节外在（非线粒体）细胞死亡信号的机制。目前，n-3 PUFA对结肠细胞凋亡影响的分子基础是一个完整的黑箱。拟议的实验代表了第一次尝试在分子水平上解释EPA和DHA的作用。