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Characterizing the signaling pathways that regulate Skp2 oncogenic function

表征调节 Skp2 致癌功能的信号通路

基本信息

批准号：
9172846
负责人：
Wenyi Wei
金额：
$ 39.57万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9172846
关键词：
Acetylation Affect Agreement Androgen Antagonists Androgens Antineoplastic Agents Automobile Driving Biochemical CCNE1 gene Cancer Patient Carcinoma Castration Cell Cycle Cell Cycle Progression Cell Line Cells Cellular Metabolic Process Citric Acid Cycle Clinical Cytoplasm Data Development Disease EP300 gene Ectopic Expression Engineering Enzymes Event Exhibits FOXO1A gene Glycolysis Growth Hormone Responsive Hormones Human In Vitro Knowledge LNCaP Lead Link Malignant Neoplasms Malignant neoplasm of prostate Mediating Metabolism Molecular Mus Neoplasm Metastasis Nude Mice Oncogenes Oncogenic Outcome Pharmacogenetics Phosphorylation Physiological Play Prostate Prostate Cancer therapy Prostate carcinoma Prostatic Neoplasms Proteins Regulation Reporting Resistance Role Signal Pathway Signal Transduction Substrate Specificity Testing Tetanus Helper Peptide Therapeutic Therapeutic Intervention Transgenic Mice Tumor Suppressor Proteins Ubiquitin Ubiquitination Withdrawal Work Xenograft Model Xenograft procedure abstracting base cancer type clinical application design in vivo inhibitor/antagonist insight mimetics mouse model mutant neoplastic cell novel novel strategies outcome forecast overexpression pre-clinical preclinical trial prostate cancer cell prostate cancer cell line prostate carcinogenesis response tumor tumor growth tumor metabolism tumor progression tumorigenesis tumorigenic ubiquitin-protein ligase

项目摘要

Abstract Skp2 is the substrate specificity factor of the SCFSkp2 E3 ligase involved in cell cycle progression through degradation of its ubiquitin targets such as p21, p27 and FOXO1. Since most of these substrates are tumor suppressor proteins, Skp2 functions as an oncogene and Skp2 overexpression is frequently observed in prostate carcinomas. However, the exact molecular mechanisms by which Skp2 induces prostate tumor growth and whether targeting Skp2 could be used as an efficient anti-prostate cancer therapy have not been fully elucidated. We recently reported that human Skp2 abundance and oncogenic functions are regulated by p300- mediated acetylation that could be antagonized by SIRT3. Moreover, expression of an acetylation-mimetic mutant of Skp2 promotes in vivo tumorigenesis in a xenograft model. We also obtained preliminary results showing that in multiple prostate cancer cell lines, Skp2 acetylation could be induced by androgen, and constitutive Skp2 acetylation might contribute to castration resistance while the underlying mechanism remains unclear. Furthermore, we identified IDH1 as a putative substrate of SCFSkp2, therefore revealing a novel role of Skp2 in cancer cell metabolism control that might underscore its oncogenic functions. Based on our preliminary data, we hypothesize that Skp2 oncogenic function is governed by acetylation, and aberrantly elevated Skp2 acetylation promotes prostate tumorigenesis and castration resistance in part by targeting downstream substrates such as IDH1 for degradation. Here, we intend to test our hypotheses by accomplishing three specific aims. In Aim #1, we will determine the molecular mechanisms by which the androgen/AR signaling pathway governs Skp2 oncogenic activity in the prostate cancer setting by regulating Skp2 acetylation. These studies will provide a novel mechanism on how androgen-induced acetylation of Skp2 regulates its oncogenic functions in the prostate cancer setting. It will also shed important insights into whether Skp2 acetylation could lead to the development of castration resistance. In Aim #2, we will examine whether acetylation of Skp2 could affect in vivo prostate cancer development using orthotopic and various engineered mouse models. These in vivo studies will significantly expand our knowledge of the regulation of Skp2 oncogenic functions by the p300/SIRT3 regulatory circuit. More importantly, we will carry out preclinical trials with MLN4924 and Skpin or compound #25 to examine if inhibiting Skp2 activity could efficiently retard in vivo prostate tumorigenesis and restore castration sensitivity. In Aim #3, we will determine the novel molecular mechanisms through which IDH1 stability is modulated by Skp2 in a Cdk2 and cell cycle dependent manner. Moreover, we will investigate whether inhibiting the Cdk2/Skp2 signaling axis could suppress prostate tumorigenesis in part by stabilizing IDH1. We believe that our proposed studies will not only provide a better molecular understanding of how Skp2 oncogenic activity is governed in vivo, but also provide direct evidence to evaluate if inactivating Skp2 could efficiently suppress prostate cancer development, leading to better treatment of this deadly disease.

摘要 Skp 2是参与细胞周期进程的SCF Skp 2 E3连接酶的底物特异性因子，其泛素靶点如p21、p27和FOXO 1的降解。由于这些基质大部分是肿瘤 Skp 2作为一种癌基因发挥功能，Skp 2的过表达经常被观察到，前列腺癌然而，Skp 2诱导前列腺肿瘤生长的确切分子机制靶向Skp 2是否可以用作有效的抗前列腺癌治疗还没有完全确定。阐明。我们最近报道了人Skp 2丰度和致癌功能受p300- 介导的乙酰化，可以被SIRT 3拮抗。此外，乙酰化模拟物的表达 Skp 2突变体在异种移植模型中促进体内肿瘤发生。我们也得到了初步的结果显示在多种前列腺癌细胞系中，Skp 2乙酰化可由雄激素诱导，组成性Skp 2乙酰化可能有助于去势抵抗，而潜在的机制仍然存在不清楚此外，我们确定IDH 1是SCFSkp 2的假定底物，因此揭示了SCFSkp 2的新作用。 skp 2在癌细胞代谢控制中的作用可能强调其致癌功能。根据我们初步的数据，我们假设Skp 2的致癌功能是由乙酰化，和异常升高Skp 2 乙酰化促进前列腺肿瘤发生和去势抵抗，部分是通过靶向下游用于降解的底物，例如IDH 1。在这里，我们打算通过完成三个测试来测试我们的假设。明确的目标。在目标#1中，我们将确定雄激素/AR信号转导的分子机制，在前列腺癌的情况下，Skp 2通路通过调节Skp 2乙酰化来控制Skp 2的致癌活性。这些研究将提供一种新的机制，雄激素诱导的Skp 2乙酰化如何调节其致癌作用，在前列腺癌中的作用。它也将揭示Skp 2乙酰化是否可以导致去势抵抗的发展。在目标#2中，我们将检查Skp 2的乙酰化是否可以使用原位和各种工程小鼠模型影响体内前列腺癌的发展。这些在体内研究将显著扩展我们对Skp 2致癌功能的调控的认识， p300/SIRT 3调节回路。更重要的是，我们将开展MLN 4924和Skpin的临床前试验，化合物#25以检查抑制Skp 2活性是否可以有效地延缓体内前列腺肿瘤发生，恢复阉割敏感性。在目标3中，我们将确定新的分子机制， IDH 1稳定性由Skp 2以Cdk 2和细胞周期依赖性方式调节。此外，我们会调查抑制Cdk 2/Skp 2信号传导轴是否可以通过稳定前列腺癌的发生来部分抑制前列腺肿瘤的发生。 IDH 1.我们相信，我们提出的研究不仅将提供一个更好的分子理解Skp 2如何致癌活性在体内受到控制，但也提供了直接证据来评估失活Skp 2是否可以有效地抑制前列腺癌的发展，从而更好地治疗这种致命的疾病。