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Mechanistic Effects of Organic Selenium Against Colon C

有机硒对结肠 C 的作用机制

基本信息

批准号：
7101888
负责人：
Mark Anthony Nelson
金额：
$ 26.02万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2007-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is the third leading cause of cancer death in both males and females in the U.S. Thus, the development of dietary and novel chemopreventive approaches for this segment of the population could provide a practical approach for significantly reducing colon cancer occurrence. Recent studies indicate that supplemental Se (in the form of high selenium containing yeast) reduces cancer risk in humans. However, the mechanism by which organic selenium exerts its anticancer effects remains to be identified. Selenomethionine is the predominant form of selenium in the yeast. We have developed evidence indicating that selenomethionine, inhibits Cox 2 protein expression in colon cancer cells. Thus, the first hypothesis to be tested is that the anticancer effects of dietary selenium (in the form of Se-yeast or selenomethionine) are mediated, in part, by inhibition of cyclooxygenase 2 (COX-2) activity. We also have evidence for a COX-2 independent mechanism. We can demonstrate alterations in cyclin A, cyclin B, and p34 cdc2 phosphorylation in selenomethionine treated colon cancer cells. These observations lead to the second hypothesis of the proposed studies that selenomethionine causes growth arrest by inappropriate expression of cyclins A and cyclins B as well increased phosphorylation of p34cdc2. To test our two main hypotheses, the three specific aims are performed 1) To determine the molecular basis of the effects of selenomethionine on COX-2 protein expression. 2: To investigate the role prostanoid receptors play in mediating the downstream effects of PGE2 in selenomethionine-induced growth inhibition. 3: To identify the mechanism for the COX-2 independent anti-cancer effects of selenium. We have a unique opportunity to translate our basic science experimental findings to clinical intervention trials. The data from these studies will identify the key mechanisms involved in the anticancer effects of selenium and increase understanding of eicosinoids in the biology of colorectal cancer. The greatest impact is realized by the provision of new molecular markers for the efficacy of selenium compounds for clinical intervention trials and the development of novel molecular targets for therapeutic intervention strategies.

描述（由申请人提供）：结直肠癌是美国男性和女性癌症死亡的第三大原因。因此，针对这部分人群开发饮食和新型化学预防方法可以为显着减少结肠癌的发生提供实用方法。最近的研究表明，补充硒（以高硒酵母的形式）可以降低人类患癌症的风险。然而，有机硒发挥抗癌作用的机制仍有待确定。硒代蛋氨酸是酵母中硒的主要形式。我们已经开发出证据表明硒代蛋氨酸可抑制结肠癌细胞中 Cox 2 蛋白的表达。因此，要测试的第一个假设是膳食硒（以硒酵母或硒代蛋氨酸的形式）的抗癌作用部分是通过抑制环氧合酶 2 (COX-2) 活性来介导的。我们还有证据表明存在 COX-2 独立机制。我们可以证明硒代蛋氨酸处理的结肠癌细胞中细胞周期蛋白 A、细胞周期蛋白 B 和 p34 cdc2 磷酸化的改变。这些观察结果引出了拟议研究的第二个假设，即硒代蛋氨酸通过细胞周期蛋白 A 和细胞周期蛋白 B 的不当表达以及 p34cdc2 磷酸化的增加导致生长停滞。为了检验我们的两个主要假设，执行了三个具体目标： 1) 确定硒代蛋氨酸对 COX-2 蛋白表达影响的分子基础。图 2：研究前列腺素受体在介导 PGE2 在硒代蛋氨酸诱导的生长抑制中的下游效应中所发挥的作用。图 3：确定硒的 COX-2 独立抗癌作用的机制。我们有一个独特的机会将我们的基础科学实验结果转化为临床干预试验。这些研究的数据将确定硒抗癌作用的关键机制，并增进对类二十烷酸在结直肠癌生物学中的了解。最大的影响是通过为临床干预试验中硒化合物的功效提供新的分子标记以及为治疗干预策略开发新的分子靶点来实现的。