anti-tumor activity of deactylase inhibitors

脱乙酰酶抑制剂的抗肿瘤活性

• 批准号: 6882614
• 负责人: MARIA L AVANTAGGIATI
• 金额: $ 28.63万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-08 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882614
• 关键词: acetylation; acyltransferase; amidohydrolases; antineoplastics; apoptosis; cell growth regulation; cell line; cytoprotection; enzyme activity; enzyme inhibitors; enzyme mechanism; flow cytometry; gene expression; gene mutation; genetic regulation; genetically modified animals; immunoprecipitation; laboratory mouse; lysine; neoplastic cell; neoplastic growth; nonhuman therapy evaluation; oncogenes; p53 gene /protein

The goal of this application is to study the molecular mechanisms underlying the anti-tumor activity of inhibitors of deacetylase enzymes (HDACs). These enzymes, which catalyze the removal of an acetyl group from the lysine residues of proteins, are well recognized to play an important role in the regulation of gene expression, and have also been implicated in malignant transformation. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that block proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models. Quite surprisingly, the effects of HDAC inhibitors seem to be somewhat selective for tumor cells and several of these compounds have now entered phase I clinical trials. From a molecular point of view, HDAC inhibition not only results in hyperacetylation of histones but also of key transcription factors such as p53, GATA-1 and estrogen receptoralpha. However thus far, the functional significance of acetylation of non-histone proteins in regulation of cell growth, and the precise mechanisms through which HDAC inhibitors induce tumor cell growth arrest remain poorly understood. We have now identified the p53 gene product as a major determinant of sensitivity to these agents, though in an unexpected way. We found that cells harboring mutations of the p53 gene, which generally confer resistance to treatment with canonical chemotherapeutic agents, are sensitive to the action of the HDAC inhibitor, TSA. We provide evidence that inhibition of HDACs, via TSA treatment, restores function from several types of p53 mutants at least in part due to p53 acetylation, and thus promotes apoptosis. By contrast, in the case of wild-type p53 acetylation of a particular residue, Lysine 320, confers chemo-protection. Based on these data we hypothesize that acetylation differentially influences the activity of wild-type and mutant forms of p53. To address this issue we will take advantage of mice genetically modified in components of the acetylation and of the p53 pathway, of unique cell types, and of a panel of p53 proteins harboring mutations at the known acetylation sites. Furthermore, we propose to identify the cellular deacetylase(s) that targets K320 and to exploit acetylation of this residue for therapeutic purposes. We expect that these studies will generate important information on the pathogenesis of cancer disease, and will provide new leads for the therapy of many types of cancer.

该应用的目的是研究脱乙酰基酶抑制剂（HDACS）抗肿瘤活性的分子机制。这些酶从蛋白质的赖氨酸残基中催化去除乙酰基，被广泛认可在基因表达的调节中起重要作用，并且也与恶性转化有关。近年来，已经鉴定出越来越多的结构上多样化的HDAC抑制剂，这些抑制剂阻断了培养物和动物模型中肿瘤细胞的分化和诱导肿瘤细胞的分化和/或凋亡。令人惊讶的是，HDAC抑制剂的作用似乎对肿瘤细胞有些选择性，现在其中几种具有 进入I期临床试验。从分子的角度来看，HDAC抑制不仅会导致 组蛋白的高乙酰化，以及关键转录因子（例如p53，GATA-1和雌激素受体）的高乙酰化。但是到目前为止，非固定蛋白在调节中的乙酰化的功能意义 细胞生长以及HDAC抑制剂诱导肿瘤细胞生长停滞的确切机制仍然鲜为人知。现在，我们已经将p53基因产物确定为对这些药物敏感性的主要决定因素，尽管以一种意外的方式。我们发现，携带p53基因突变的细胞（通常允许使用规范化学治疗剂）具有耐药性，对HDAC抑制剂TSA的作用敏感。我们提供的证据表明，通过TSA处理，抑制HDAC至少部分是由于p53乙酰化恢复了几种类型的p53突变体的功能，从而促进了凋亡。相比之下，在特定残基的野生型p53乙酰化的情况下，赖氨酸320 化学保护。基于这些数据，我们假设乙酰化会差异地影响p53的野​​生型和突变体形式的活性。为了解决这个问题，我们将利用在乙酰化和p53途径（独特细胞类型的p53途径）中进行基因修饰的小鼠，以及在已知的乙酰化位点具有突变的p53蛋白。此外，我们建议确定针对K320并利用该残基的乙酰化的细胞脱乙酰基酶来治疗目的。我们预计这些研究将产生有关癌症发病机理的重要信息，并为治疗多种类型的癌症提供新的潜在客户。