anti-tumor activity of deacetylase inhibitors

脱乙酰酶抑制剂的抗肿瘤活性

• 批准号: 6784351
• 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/6784351
• 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.

本应用的目的是研究脱乙酰酶抑制剂(HDACs)抗肿瘤活性的分子机制。这些酶催化蛋白质赖氨酸残基上的乙酰基的去除，被公认为在基因表达调控中发挥重要作用，也与恶性转化有关。近年来，在培养和动物模型中发现了越来越多的结构多样化的HDAC抑制剂，它们可以阻断肿瘤细胞的增殖并诱导其分化和/或凋亡。非常令人惊讶的是，HDAC抑制剂的作用似乎对肿瘤细胞有一定的选择性，其中几种化合物现在已经做到了。 进入I期临床试验。从分子的角度来看，抑制HDAC不仅会导致 组蛋白的高乙酰化，以及关键转录因子如P53、GATA-1和雌激素受体α的高乙酰化。然而，到目前为止，非组蛋白乙酰化在调节细胞周期中的功能意义。 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知之甚少。我们现在已经确定p53基因产物是对这些药物敏感性的主要决定因素，尽管是以一种意想不到的方式。我们发现，携带p53基因突变的细胞对HDAC抑制剂TSA的作用敏感，这种突变通常会导致对规范化疗药物的治疗产生抗药性。我们提供的证据表明，通过抑制HDACs，通过TSA治疗，可以恢复几种类型的p53突变的功能，至少部分是由于p53乙酰化，从而促进细胞凋亡。相比之下，在特定残基赖氨酸320的野生型p53乙酰化的情况下， 化学防护剂。基于这些数据，我们假设乙酰化对野生型和突变型P53的活性有不同的影响。为了解决这个问题，我们将利用转基因小鼠的乙酰化和p53途径的组成部分，独特的细胞类型，以及一组在已知乙酰化位置存在突变的p53蛋白。此外，我们建议鉴定针对K320的细胞脱乙酰酶(S)，并将该残基的乙酰化用于治疗目的。我们期待这些研究将产生关于癌症发病机制的重要信息，并将为许多类型的癌症的治疗提供新的线索。