Detection of Novel Polyamine Analogs with Anti-Prostate Cancer Activity

描述(申请人提供)：多胺分解代谢酶精胺/精胺-N1-乙酰转移酶(SSAT)的合成已知随着多胺的增加而迅速增加，我们的新数据解释了负责这一反应的蛋白质翻译控制机制。我们发现，核仁异构体通过与mRNA ORF末端的茎环结合来抑制翻译，并且在暴露于外源性多胺的细胞中，这种异构体被降解。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‘非编码区在上游ORF结构性抑制翻译中也起作用。由于多胺对癌细胞生长是必不可少的，刻意诱导SSAT是一种正在进行的抗癌策略。 因此，我们对SSAT翻译控制的新认识表明，去抑制是一个抗癌的靶点，特别是对前列腺癌，因为多胺途径在这个器官中非常活跃。我们建议检验这样一种假设，即检测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品化合物。我们计划首先验证我们开发的一种基于细胞的分析，该细胞将SSAT表达为融合蛋白和报告蛋白。在用这种方法筛选文库后，那些被发现抑制SSAT的化合物将在第二次筛选中进行抗增殖活性的检查。我们的目标是确定8-10种新的化合物，这些化合物可以解除抑制SSAT并抑制前列腺癌细胞系的增殖。

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.