Overcoming EMT-driven metastatic castration-resistant prostate cancer

克服 EMT 驱动的转移性去势抵抗性前列腺癌

基本信息

批准号：
9377994
负责人：
Gnanasekar Munirathinam
金额：
$ 8万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9377994
关键词：
Ablation Adjuvant Adverse effects Alkaloids Androgen Receptor Androgens Antimetastatic Agent Apoptotic Biological Assay Body part Cancer Etiology Cancer Patient Capsicum Cell Culture System Cells Cessation of life Clinical DU145 Death Rate Development Diet Down-Regulation E-Cadherin Fibronectins Foundations Future Gene Silencing Genetic Transcription Grant Histopathology Hormones Immunohistochemistry In Vitro Intravenous LNCaP Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Modeling Molecular N-Cadherin Neoplasm Metastasis Nude Mice Operative Surgical Procedures Organ PC3 cell line PSA level Patients Pharmacology Pilot Projects Play Pre-Clinical Model Prevention Process Property Prostate Prostatic Neoplasms Proteins Publications Radiation therapy Recurrent Malignant Neoplasm Regulation Reporting Role Signal Transduction Snails Solid Spices Stress TPT1 gene Testing Time Tissue Sample Toxic effect Tumor Suppressor Proteins United States Vimentin alternative treatment androgen deprivation therapy androgen sensitive base cancer cell castration resistant prostate cancer chemotherapy epithelial to mesenchymal transition gain of function hormone therapy in vitro Model in vivo men migration mouse model piperine prevent promoter prostate cancer cell therapeutic target therapy development translational study treatment choice treatment strategy tumor tumor growth

项目摘要

Summary: Prostate cancer (PCa) that initially develops in the prostate gland is curable by surgery and radiotherapy. The standard choice of treatment for PCa is by androgen ablation since PCa cells survive on the availability of androgen hormone. Although this treatment approach is effective initially, PCa recur invariably and do not respond to hormonal therapy. However when the cancer has spread to other parts of the body and such form of recurrent cancer known as metastatic castration-resistant prostate cancer (CRPC) is practically incurable and lethal. Hence, there is an urgent need to develop effective and safe anti-cancer alternatives such as compounds derived from diet to successfully control CRPC. Piperine (PIP), a natural alkaloid abundantly present in pepper spice has several pharmacological benefits including anti-cancer activity. Our recent publication for the first time showed that PIP inhibits both hormone-dependent and hormone-independent prostate tumor growth in nude mice model. Importantly, we showed that PIP down regulates the expression of androgen receptor (AR) resulting in the reduction of PSA levels in PCa cells. However, whether PIP has anti-metastatic properties in CRPC cells are not known. Our subsequent preliminary studies identified that PIP targets the transcription of Translationally Controlled Tumor Protein (TCTP), an anti-apoptotic protein that promotes the metastatic properties of CRPC cells. Downregulation of TCTP by PIP also results in the activation of E-cadherin, a tumor suppressor molecule in CRPC cells by modulating the expression of key epithelial to mesenchymal transition (EMT) markers such as snail-1 and N-cadherin. Based on these observations, our hypothesis is that dietary administration of PIP can inhibit metastasis development by targeting AR, TCTP and reversing EMT signaling in CRPC cells. This hypothesis will be tested in two specific aims. In Aim 1, we will determine whether dietary administration of PIP can inhibit or prevent metastasis of C4-2B RFP and 22Rv1 RFP cells in an experimental intravenous metastasis model of nude mice. In these studies, tumor metastasis will be used as end points. At the end of the study, metastatic lesions and various organs will be collected for histopathology analyses to determine the effects of PIP on metastasis. Expression of TCTP, AR, α-SMA, fibronectin, snail-1, N-cadherin, vimentin and E-cadherin in the metastatic tissue samples will also be determined by immunohistochemistry. In Aim 2, we will delineate whether PIP disrupts AR and TCTP-mediated EMT signaling to restore E-cadherin as a mechanism to target metastatic CRPC cells in an in vitro model. In this aim, we will use variety of approaches such as gene silencing, gain of function, pharmacological, promoter and molecular based assays to delineate the anti-metastatic mechanisms of PIP. Results obtained upon successful completion of these proposed specific aims will yield valuable information in developing PIP as a potential anti-metastatic agent in successfully controlling CRPC.

概括：最初在前列腺中发生的前列腺癌 (PCa) 可通过手术治愈 PCa 的标准治疗选择是雄激素消融。因为 PCa 细胞依靠雄激素的存在而生存。治疗方法最初有效，PCa 总是复发且没有反应然而，当癌症已经扩散到身体的其他部位并且这种形式的复发性癌症称为转移性去势抵抗性前列腺癌（CRPC）实际上是无法治愈且致命的，因此迫切需要开发。有效且安全的抗癌替代品，例如从饮食中提取的化合物成功控制 CRPC（PIP），一种富含于体内的天然生物碱。胡椒香料具有多种药理功效，包括抗癌活性。最近发表的文章首次表明 PIP 抑制激素依赖性重要的是，我们在裸鼠模型中进行了激素非依赖性前列腺肿瘤生长。表明 PIP 下调雄激素受体 (AR) 的表达，导致然而，PIP是否具有抗转移作用。我们随后的初步研究确定了 CRPC 细胞的特性。 PIP 靶向翻译控制肿瘤蛋白 (TCTP) 的转录，一种抗凋亡蛋白，可促进 CRPC 细胞的转移特性。 PIP 下调 TCTP 也会导致 E-钙粘蛋白（一种肿瘤）的激活 CRPC细胞中的抑制分子通过调节关键上皮细胞的表达间质转化 (EMT) 标记物，例如 snail-1 和 N-钙粘蛋白。根据这些观察结果，我们的假设是，饮食中给予 PIP 可以抑制通过靶向 AR、TCTP 和逆转 CRPC 中的 EMT 信号来促进转移在目标 1 中，我们将确定这一假设。饮食中给予 PIP 是否可以抑制或预防 C4-2B RFP 的转移和22Rv1 RFP细胞在实验性裸鼠静脉转移模型中的应用。在这些研究中，肿瘤转移将被用作终点。将收集转移病灶和各种器官进行组织病理学分析，以确定 PIP 对 TCTP、AR、α-SMA 表达的影响。转移组织中的纤连蛋白、snail-1、N-钙粘蛋白、波形蛋白和 E-钙粘蛋白样本也将通过免疫组织化学进行测定。在目标 2 中，我们将描述。 PIP 是否会破坏 AR 和 TCTP 介导的 EMT 信号传导以恢复 E-钙粘蛋白作为在体外模型中，我们将使用靶向转移性 CRPC 细胞的机制。多种方法，如基因沉默、功能获得、药理学、启动子和基于分子的测定来描述抗转移机制 PIP。成功完成这些拟议的具体目标后获得的结果将在开发 PIP 作为潜在抗转移剂方面提供了有价值的信息成功控制CRPC。