Mechanistic Effects of Organic Selenium Against Colon C

描述(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，为这部分人群开发饮食和新的化学预防方法可以为显著减少结肠癌的发生提供一种实用的方法。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，有机硒发挥抗癌作用的机制尚不清楚。硒蛋氨酸是酵母中硒的主要存在形式。我们已有证据表明，硒蛋氨酸可以抑制结肠癌细胞中COX-2蛋白的表达。因此，要检验的第一个假设是，膳食硒(以硒酵母或硒蛋氨酸的形式)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。我们也有证据表明存在COX-2独立机制。我们可以证明，在硒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p34cdc2的磷酸化发生了变化。这些观察结果导致了拟议研究的第二个假设，即硒蛋氨酸通过不适当地表达周期蛋白A和周期蛋白B以及增加p34cdc2的磷酸化来导致生长停滞。为了验证我们的两个主要假设，三个特定的目的被执行：1)确定硒蛋氨酸影响COX-2蛋白表达的分子基础。2.探讨前列腺素受体在PGE2对硒蛋氨酸诱导的细胞生长抑制中的下游作用。3.探讨硒对COX-2非依赖性抗癌作用的机制。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的抗癌作用所涉及的关键机制，并增加对结直肠癌生物学中二十烷基类化合物的了解。最大的影响是为临床干预试验提供了新的硒化合物疗效的分子标记，并为治疗干预策略开发了新的分子靶标。

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.