Regulation of Prostate Cancer Growth by PPARg Ligands

PPARg 配体对前列腺癌生长的调节

基本信息

批准号：
7846187
负责人：
LaMonica Vanette Stewart
金额：
$ 15.14万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846187
关键词：
2,4-thiazolidinedione Agonist Androgen Receptor Androgens Animal Model Animals Apoptosis Cancer Cell Growth Cell Cycle Progression Cell Proliferation Chromatin Clinical Trials Combined Modality Therapy Complex Cyclin D1 Cyclin-Dependent Kinase Inhibitor Data Down-Regulation Gene Expression Genes Genetic Transcription Goals Growth Human In Vitro Ligands Malignant neoplasm of prostate Mediating Modeling Nude Mice PC3 cell line PPAR gamma Pathway interactions Patients Pharmaceutical Preparations Prostatic Neoplasms Proteins Regulation Research Design Role Signal Pathway Small Interfering RNA Testing Thiazolidinediones Treatment Protocols Up-Regulation Vitamin D Analog Vitamin D3 Receptor Work Xenograft Model angiogenesis cancer cell cancer therapy cell type ciglitazone design in vivo overexpression protein expression receptor function research study tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to define how thiazolidinediones (TZDs) and other ligands for the peroxisome proliferator activated receptor gamma (PPARg) could be used clinically to treat patients with prostate cancer. Although PPARg ligands have been shown to reduce proliferation of human prostate cancer cells in vitro and inhibit prostate tumor growth in vivo, the mechanisms by which these reductions in proliferation and tumor growth occur are not fully understood. As a result, it is difficult to determine which patients would benefit from treatment regimens involving PPARg ligands. It is my hypothesis that TZDs and other PPARg ligands reduce prostate cancer cell proliferation by inhibiting the function of the androgen receptor (AR) as well as by inducing AR-independent alterations in gene expression. The experiments in this proposal are designed to test this hypothesis by examining the effects of TZDs such as ciglitazone on human prostate cancer cell lines both in vitro and in vivo. In Aim 1, we will define the mechanisms by PPARg ligands inhibit AR function in human prostate cancer cell lines. In this studies we will examine not only the effects of TZDs on androgen-induced gene expression but also the ability of TZDs to regulate the assembly of AR transcriptional complexes on chromatin. In Aim 2, we will test the hypothesis that PPARg ligands inhibit prostate cancer cell proliferation by altering expression of proteins that regulate cell cycle progression. To accomplish this aim, we will determine the importance of cyclin D1 down-regulation in TZDinduced decreases in cell proliferation. In addition we will explore whether TZDs induce expression of cyclin dependent kinase inhibitors and define the role of this up-regulation in the TZD anti-proliferative effect. In Aim 3, we will use an athymic mouse xenograft model to determine whether combination treatments involving PPARg ligands and vitamin D receptor agonists are effective at reducing growth of human prostate tumors in vivo. The data obtained from these studies will provide us with new information regarding the signaling pathways activated by PPARg ligands within human prostate cancer cells. In addition, these data will demonstrate how PPARg ligands can be used alone or in combination with other drugs to treat prostate cancer. This information can then be used to design prostate cancer treatments involving PPARg ligands that can be tested initially in animal models and then further explored in clinical trials.

描述（由申请人提供）：该项目的长期目标是确定噻唑烷二酮类（TZD）和过氧化物酶体增殖物激活受体γ（PPARg）的其他配体如何在临床上用于治疗前列腺癌患者。尽管 PPARg 配体已被证明可以在体外减少人前列腺癌细胞的增殖并在体内抑制前列腺肿瘤的生长，但这些增殖和肿瘤生长减少的机制尚不完全清楚。因此，很难确定哪些患者会受益于 PPARg 配体的治疗方案。我的假设是，TZD 和其他 PPARg 配体通过抑制雄激素受体 (AR) 的功能以及诱导与 AR 无关的基因表达改变来减少前列腺癌细胞增殖。本提案中的实验旨在通过检查 TZD（例如环格列酮）对体外和体内人类前列腺癌细胞系的影响来检验这一假设。在目标 1 中，我们将定义 PPARg 配体抑制人前列腺癌细胞系中 AR 功能的机制。在这项研究中，我们不仅将研究 TZD 对雄激素诱导的基因表达的影响，还将研究 TZD 调节染色质上 AR 转录复合物组装的能力。在目标 2 中，我们将检验以下假设：PPARg 配体通过改变调节细胞周期进程的蛋白质表达来抑制前列腺癌细胞增殖。为了实现这一目标，我们将确定细胞周期蛋白 D1 下调在 TZD 诱导的细胞增殖减少中的重要性。此外，我们将探讨 TZD 是否诱导细胞周期蛋白依赖性激酶抑制剂的表达，并确定这种上调在 TZD 抗增殖作用中的作用。在目标 3 中，我们将使用无胸腺小鼠异种移植模型来确定涉及 PPARg 配体和维生素 D 受体激动剂的联合治疗是否能有效减少体内人类前列腺肿瘤的生长。从这些研究中获得的数据将为我们提供有关人前列腺癌细胞内 PPARg 配体激活的信号通路的新信息。此外，这些数据将证明PPARg配体如何单独使用或与其他药物联合使用来治疗前列腺癌。然后，该信息可用于设计涉及 PPARg 配体的前列腺癌治疗方法，这些治疗方法可首先在动物模型中进行测试，然后在临床试验中进一步探索。