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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8525356
• 关键词: 5' Untranslated Regions; Anabolism; Antineoplastic Agents; Binding; Biological Assay; Cancer Cell Growth; Cells; Chimeric Proteins; Data; Detection; Enzymes; Feedback; Food; Goals; Human; Knowledge; Lead; Libraries; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Metabolism; Open Reading Frames; Organ; PC3 cell line; Pathway interactions; Play; Polyamine Catabolism; Polyamines; Protein Isoforms; Proteins; Reporter; Reporter Genes; Repression; Role; Spermidine/Spermine N1-Acetyltransferase; Structure; System; Testing; Translations; analog; base; novel; nucleolin; pharmacophore; response; screening; stem

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精子/精子-N1-乙酰转移酶（SSAT）的合成已知会因增加多胺而迅速增加，而我们的新数据解释了负责此反应的蛋白质翻译控制机制。我们表明，核仁蛋白的同工型通过在mRNA ORF的极端5'末端与茎环的结合来抑制翻译，并且该同工型在暴露于外源性多胺的细胞中降解。这提供了负反馈控制，因为增加的多胺会诱导多胺分解代谢。 5'UTR也在上游ORF的组成型抑制翻译中起作用。由于多胺对于癌细胞生长至关重要，因此故意诱导SSAT是一种持续的抗癌策略。 因此，我们对SSAT翻译控制的新知识将消除抑制作为抗癌靶标，尤其是对于前列腺癌，因为多胺途径在该器官中高度活跃。我们提出了测试以下假设：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品化合物。我们计划首先验证我们基于将SSAT作为融合蛋白表达与报告蛋白的融合蛋白的细胞开发的测定。使用此测定法筛选库后，将在二级筛选中检查发现抑制SSAT的这些化合物是否进行抗增殖活性。我们的目的是鉴定8-10种新型化合物，这些化合物可以抑制SSAT并抑制前列腺癌细胞系的增殖。

项目成果

A novel assay platform for the detection of translation modulators of spermidine/spermine acetyltransferase.

用于检测亚精胺/精胺乙酰转移酶翻译调节剂的新型检测平台。

• DOI: 10.2174/13816128113199990035
• 发表时间: 2014
• 期刊: Current pharmaceutical design
• 影响因子: 3.1
• 作者: Perez-Leal,Oscar;Abou-Gharbia,Magid;Gordon,John;Childers,WayneE;Merali,Salim
• 通讯作者: Merali,Salim