Mechanistic Effects of Organic Selenium Against Colon C

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，针对这部分人群的饮食和新型化学预防方法的发展可以为显着减少结肠癌的发生提供实用的方法。最近的研究表明，补充硒（以高含硒酵母的形式）可以降低人类患癌症的风险。然而，有机硒发挥其抗癌作用的机制尚不清楚。硒代蛋氨酸是酵母中硒的主要形式。我们已经有证据表明硒代蛋氨酸可以抑制结肠癌细胞中Cox 2蛋白的表达。因此，需要验证的第一个假设是，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化酶2 （COX-2）活性介导的。我们也有证据表明COX-2独立的机制。我们可以证明在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磷酸化发生了变化。这些观察结果导致提出的研究的第二个假设，即硒代蛋氨酸通过不适当表达细胞周期蛋白A和细胞周期蛋白B以及增加p34cdc2的磷酸化而导致生长停滞。为了验证我们的两个主要假设，我们实现了三个具体目标：1)确定硒代蛋氨酸对COX-2蛋白表达影响的分子基础。2：探讨前列腺素受体介导PGE2在硒代蛋氨酸诱导的生长抑制中的下游作用。3：明确硒的COX-2非依赖性抗癌作用机制。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，并增加对结直肠癌生物学中类二十烷酸的理解。最大的影响是为临床干预试验提供新的硒化合物疗效分子标记，并为治疗干预策略开发新的分子靶点。

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.