COLONIC CYTOKINETICS AND CELL SIGNALING--DIETARY EFFECT

在饮食因素中，有很强的流行病学、临床和 实验数据表明对n-3病毒有保护作用 多不饱和脂肪酸(n-3多不饱和脂肪酸；二十碳五烯酸，20：5n- 3和二十二碳六烯酸，22：N-3)治疗结肠癌。我们有 最近证明，饮食中的n-3多不饱和脂肪酸具有保护作用 对抗实验性的致癌作用，即减少肿瘤 发病率，部分是通过以下方式增加细胞的删除 激活细胞凋亡，这可能会减少基因的积累 错误。这些数据支持我们的假设，饮食中的n-3多不饱和脂肪酸起作用 作为抗癌物质，通过促进细胞凋亡去除 致癌物质加成的细胞。为了进一步阐明 N-3PUFAs诱导细胞凋亡的机制(S)。我们将利用 高相关大鼠结肠癌发生模型的建立 N-3多不饱和脂肪酸是否调节DNA加合物的形成、去除(DNA修复) 和/或缺失(细胞凋亡)在恶性肿瘤的早期阶段 转型。我们最近还表明，n-3多不饱和脂肪酸可以防止 致癌物诱导的结肠蛋白慢性下调 激酶C(PKC)Delta(新的)、Zeta(非典型的)和选择性Up- PKC BetaII的调控(经典)。这一点意义重大，因为 隐窝蛋白激酶C水平的维持可能维持体内平衡 细胞增殖和凋亡之间的平衡。因此，我们有 假设n-3多不饱和脂肪酸通过以下方式降低结肠癌发病率 阻断致癌物对结肠PKC同工酶的影响 信号转导。为了进一步确定n-3的意义 PUFA诱导的结肠PKC表达的变化，我们将阐明 特异性PKC同工酶在结肠癌发生发展中的作用 体内靶向药物抑制物联合应用 体外过度表达和反义策略。澄清： 膳食n-3多不饱和脂肪酸降低结肠癌发病率的机制(S) 将导致建立饮食指南，旨在 降低结肠癌发病率和死亡率。这项实验 方法尤其相关，因为尽管在 结肠癌的治疗，5年死亡率并没有 在过去的40年里取得了显著的进步。因此， 必须制定化学预防饮食策略，以便 降低患结肠癌的风险。

Among dietary factors, there is strong epidemiological, clinical and experimental data indicating a protective effect on n-3 polyunsaturated fatty acids (n-3 PUFAs; eicosapentaenoic acid, 20:5n- 3 and docosahexaenoic acid, 22:n-3) on colon cancer. We have recently demonstrated that dietary n-3 PUFAs confer protection against experimental carcinogenesis, i.e., a reduction in tumor incidence, in part by enhancing the deletion of cells through activation of apoptosis, which may reduce the accumulation of genetic errors. These data support our postulate that dietary n-3 PUFAs act as anticarcinogens by facilitating the apoptotic removal of carcinogen adducted cells. In order to further elucidate the mechanism(s) by which n-3 PUFAs-induce apoptosis. We will utilize the highly relevant rat model of colon carcinogenesis to determine whether n-3 PUFAs modulate DNA adduct formation, removal (DNA repair) and/or deletion (apoptosis) during the initial stages of malignant transformation. We have also recently show that n-3 PUFAs prevent the carcinogen-induced chronic down-regulation of colonic protein kinase C (PKC) delta (novel), zeta (atypical), and the selective up- regulation of PKC betaII (classical). This is significant because the maintenance of crypt PKC levels may sustain the homeostatic balance between cell proliferation and apoptosis. Therefore, we have hypothesized that n-3 PUFAs reduce colon cancer incidence in part by blocking the effects of carcinogen on colonic PKC isozyme-related signal transduction. To further determine the significance of n-3 PUFA-induced changes in colonic PKC expression, we will elucidate the role of specific PKC isozymes in colon tumor development by using a targeted pharmacological inhibitor in vivo in combination with overepression and antisense strategies in vitro. Elucidation of the mechanism(s) by which dietary n-3 PUFAs reduce colon cancer incidence will lead to the establishment of dietary guidelines designed to reduce colon cancer morbidity and mortality. This experimental approach is particularly relevant because despite advancement in the treatment of colon cancer, the 5 year mortality rate has not appreciable improved over the past 4 decades. Therefore, chemopreventive dietary strategies must be developed in order to decrease the risk of colon cancer.