Detection of Novel Polyamine Analogs with Anti-Prostate Cancer Activity

具有抗前列腺癌活性的新型多胺类似物的检测

基本信息

批准号：
8525356
负责人：
SALIM MERALI
金额：
$ 15.64万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-07 至 2015-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Synthesis of the polyamine catabolic enzyme spermidine/spermine-N1-acetyltransferase (SSAT) has been known to increase rapidly in response to increased polyamines and our new data explain the protein translation control mechanism responsible for this response. We showed that an isoform of nucleolin represses translation by binding to a stem-loop at the extreme 5' end of the mRNA ORF and that this isoform is degraded in cells exposed to exogenous polyamines. This provides negative feedback control in that increased polyamines induce polyamine catabolism. The 5' UTR is also plays a role in that upstream ORF's constitutively suppress translation. Since polyamines are essential for cancer cell growth, deliberate induction of SSAT is an ongoing anti-cancer strategy. Therefore our new knowledge of SSAT translation control presents de-repression as an anti-cancer target, especially for prostate cancer since the polyamine pathway is highly active in this organ. We propose testing the hypothesis that a system to detect SSAT translation de-repression will identify bioactive food compounds with anti-proliferative activity. We plan first t validate an assay we developed based on cells that express SSAT as a fusion protein with a reporter protein. After screening a library using this assay, those compounds found to de-repress SSAT will be examined in secondary screen for anti-proliferative activity. Our aim is to identify 8-10 novel compounds that de-repress SSAT and inhibit proliferation of a prostate cancer cell line.

描述（由申请人提供）：已知多胺分解代谢酶亚精胺/精胺-N1-乙酰转移酶（SSAT）的合成会随着多胺的增加而迅速增加，我们的新数据解释了导致这种反应的蛋白质翻译控制机制。我们发现，核仁素的同工型通过与 mRNA ORF 5' 末端的茎环结合来抑制翻译，并且该同工型在暴露于外源多胺的细胞中会被降解。这提供了负反馈控制，因为增加的多胺诱导多胺分解代谢。 5' UTR 还在上游 ORF 组成型抑制翻译中发挥作用。由于多胺对于癌细胞生长至关重要，因此有意诱导 SSAT 是一种持续的抗癌策略。因此，我们对 SSAT 翻译控制的新认识将去抑制作为抗癌靶标，特别是对于前列腺癌，因为多胺途径在该器官中高度活跃。我们建议测试以下假设：检测 SSAT 翻译去抑制的系统将识别具有抗增殖活性的生物活性食物化合物。我们计划首先验证我们开发的基于表达 SSAT 与报告蛋白融合蛋白的细胞的检测方法。使用此测定法筛选文库后，将在二次筛选中检查那些发现去抑制 SSAT 的化合物的抗增殖活性。我们的目标是鉴定 8-10 种能够解除 SSAT 抑制并抑制前列腺癌细胞系增殖的新型化合物。