Regulation of Prostate Cancer Growth by PPARg Ligands

描述(由申请人提供)：该项目的长期目标是确定噻唑烷二酮(TZDS)和其他过氧化物酶体增殖物激活受体γ(PPARg)的配体如何用于临床治疗前列腺癌患者。虽然PPARg配体已被证明在体外可以抑制人前列腺癌细胞的增殖，并在体内抑制前列腺癌的生长，但这些抑制增殖和肿瘤生长的机制还不完全清楚。因此，很难确定哪些患者将从使用PPARg配体的治疗方案中受益。我的假设是，TZDS和其他PPARg配体通过抑制雄激素受体(AR)的功能以及通过诱导AR非依赖性的基因表达变化来抑制前列腺癌细胞的增殖。这项建议中的实验旨在通过检测TZDS(如西格列酮)在体外和体内对人类前列腺癌细胞株的影响来检验这一假设。在目标1中，我们将确定PPARg配体抑制人前列腺癌细胞株AR功能的机制。在这项研究中，我们不仅将研究TZDS对雄激素诱导的基因表达的影响，还将研究TZDS调节AR转录复合体在染色质上组装的能力。在目标2中，我们将验证PPARg配体通过改变调节细胞周期进程的蛋白质的表达来抑制前列腺癌细胞增殖的假设。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，我们还将探讨TZD是否能诱导细胞周期蛋白依赖性激酶抑制物的表达，并确定这种上调在TZD抗增殖作用中的作用。在目标3中，我们将使用裸鼠异种移植模型来确定包括PPARg配体和维生素D受体激动剂的联合治疗是否在体内有效地减少人类前列腺癌的生长。从这些研究中获得的数据将为我们提供关于PPARg配体在人前列腺癌细胞内激活的信号通路的新信息。此外，这些数据将展示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，这些信息可以用来设计涉及PPARg配体的前列腺癌治疗方法，这些配体可以最初在动物模型中进行测试，然后在临床试验中进一步探索。

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.