POLYAMINE ANALOG REGULATION OF CELL CYCLE AND APOPTOSIS

细胞周期和细胞凋亡的多胺模拟调节

基本信息

批准号：
7227133
负责人：
CARL W PORTER
金额：
$ 34.47万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-08-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7227133
关键词：
Acetyltransferase Anabolism Antineoplastic Agents Apoptosis Apoptotic Cell Cycle Arrest Cell Cycle Regulation Cell Line Cell Proliferation Cells Condition Drug Combinations Drug effect disorder Elements Enzymes Event Gene Expression Profiling Genes Goals Grant Growth Link Maps Mediating Melanoma Cell Metabolic N(1),N(11)-bis(ethyl)norspermine Other Finding Outcome Paper Pathway interactions Pharmaceutical Preparations Platinum Compounds Play Polyamine Catabolism Polyamines Protein Overexpression RNA Interference Relative (related person)Role Series Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA Spermidine/Spermine N1-Acetyltransferase Supporting Cell System TP53 gene Technology Therapeutic Xenograft procedure analog base clinically relevant in vivo inhibitor/antagonist polyamine oxidase response tumor growth

项目摘要

DESCRIPTION (provided by applicant): Polyamines are well recognized for their critical role in supporting cell proliferation-a role that has been preclinically validated as a worthy anticancer target. During the past granting period, we have described the signaling, effectors and survival responses elicited by polyamine inhibitors or analogs in arrest-prone MALME-3M melanoma cells and in apoptosis-prone SK-MEL-28 cells. In the case of analogs, potent induction of the catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT), emerged as the key initiator of metabolic and signaling events that culminate in apoptosis or cell cycle arrest. That linkage was confirmed by SSAT-targeted RNAi, making DENSPM the only polyamine analog having a defined mechanism of growth inhibition. In pursuit of downstream metabolic events, we have genomically identified and biochemically characterized (a) an analog-inducible spermine oxidase, (b) an analog-inducible polyamine oxidase, and (c) a second SSAT. Taken together, these various findings present converging opportunities for investigating how analog induction of polyamine catabolism relates to apoptosis and cell cycle arrest and for devising mechanism-based strategies for exploiting these findings towards a therapeutic advantage. The following Specific Aims pursue these significant new leads in the same two melanoma cells with the goal of determining how inducible polyamine catabolic systems mechanistically interface with recently defined pathways of cell cycle arrest and apoptosis. Aim 1 will determine the relative contribution of new polyamine catabolic enzymes in analog-induced apoptosis of SK-MEL-28 cells; Aim 2 will identify downstream signaling molecules linking polyamine catabolism to apoptosis in analog treated SK-MEL-28 cells; Aim 3 will determine the relative contribution of p53 and new polyamine catabolic enzymes in analog-induced cell cycle arrest of MALME-3M cells; Aim 4 will identify downstream signaling molecules linking polyamine catabolism to apoptosis in analog treated MALME-3M cells, and Aim 5 will validate the role of polyamine catabolic enzymes in mediating or contributing to DENSPM antitumor activity.

描述（由申请人提供）：多胺在支持细胞增殖中的关键作用被广泛认可，该作用已被临时证实为有价值的抗癌靶标。在过去的给予期间，我们描述了多胺抑制剂或类似物在容易被逮捕的Malme-3M黑色素瘤细胞和易凋亡易凋亡的SK-MEL-28细胞中引起的信号传导，效应子和生存反应。在类似物的情况下，有效诱导分解代谢酶，精子/精子N1-乙酰基转移酶（SSAT），成为代谢和信号事件的关键起点，这些事件在凋亡或细胞周期停滞中达到顶峰。 SSAT靶向的RNAi证实了这种联系，使denSPM成为具有生长抑制的定义机制的唯一多胺类似物。为了追求下游的代谢事件，我们在基因组上鉴定并在生物化学上表征了（a）类似物诱导的精子氧化酶，（b）类似物诱导的多胺氧化酶，以及（c）第二个SSAT。综上所述，这些各种发现提供了调查多胺分解代谢与细胞凋亡和细胞周期停滞的关系的融合机会，并制定了基于机制的策略，以利用这些发现来获得治疗优势。以下特定目的在相同的两个黑色素瘤细胞中追求这些重要的新导线，目的是确定诱导型多胺分解代谢系统如何与最近定义的细胞周期停滞和凋亡途径进行机械界面。 AIM 1将确定新的多胺分解代谢酶在类似物诱导的SK-MEL-28细胞凋亡中的相对贡献； AIM 2将识别将多胺分解代谢与模拟处理过的SK-MEL-28细胞中凋亡联系起来的下游信号分子； AIM 3将确定p53和新的多胺分解代谢酶在类似物诱导的Malme-3M细胞的细胞周期停滞中的相对贡献； AIM 4将识别将多胺分解代谢与模拟处理的Malme-3M细胞中的凋亡联系起来的下游信号分子，AIM 5将验证多胺分解代谢酶在介导或有助于denspm抗肿瘤活性中的作用。