TIMP3: A Molecular Target of Green Tea Polyphenols

TIMP3：绿茶多酚的分子靶点

基本信息

批准号：
9099803
负责人：
SANJAY GUPTA
金额：
$ 20.68万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099803
关键词：
Acetylation Basement membrane Binding Biological Assay Biological Markers Breast cancer metastasis Cancer Patient Catalytic Domain Cause of Death Cell Culture Techniques Cells ChIP-seq Clinical Clinical Trials Colon Carcinoma Complex Consumption Data Deacetylation Development Disease Disease-Free Survival Down-Regulation Enhancers Enzymes Epigallocatechin Gallate Epigenetic Process Extracellular Matrix Degradation Gelatinase A Genetic Genomics Global Change Goals HGF gene Health Histone Deacetylase Inhibitor Histones Home environment Homologous Gene Human In Vitro Incidence Kidney Knowledge Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Malignant neoplasm of prostate Matrix Metalloproteinases Mediating Medical Metastatic Prostate Cancer Modality Modeling Modification Molecular Molecular Target Monitor Mus Neoplasm Metastasis Organ Patients Peptide Hydrolases Phenotype Polycomb Pre-Clinical Model Preventive Primary Neoplasm Process Prostatic Neoplasms Protein Subunits Proteins Recurrence Repression Role SCID Mice Staging Supplementation Surrogate Endpoint TIMP3 gene Tissue Inhibitor of Metalloproteinases Trichostatin A Tumor Angiogenesis Tumor Cell Invasion Tumor Suppressor Proteins Up-Regulation Vascular Endothelial Growth Factors Work base bone cancer cell clinical investigation cost cost effective histone methylation histone modification implantation improved in vivo inhibitor/antagonist knock-down metastasis prevention metastatic process mortality neoplastic cell novel novel marker novel strategies novel therapeutics overexpression prevent promoter prostate cancer cell prostate cancer model protein expression research study soft tissue stoichiometry survivorship tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The overall goals of this proposal is to understand the mechanisms by which green tea polyphenols and its major constituent (-)-epigallocatechin-3-gallate inhibits prostate cancer metastasis. Consumption of green tea polyphenols (GTP) is effective in the development and could delay the progression of prostate cancer at its outset. However, the molecular mechanism(s) by which green tea polyphenols and its major constituent, epigallocatechin-3-gallate (EGCG) suppresses the metastatic process has not been completely understood. Metastasis is a complex multistep process that involves degradation of extracellular matrix through induction of proteolytic enzymes viz. matrix metalloproteinases (MMPs) and downregulation of their binding partner tissue inhibitor of metalloproteinases (TIMPs) critical for invasion and dissemination of malignant cells. Our preliminary studies demonstrate that GTP/EGCG-mediated tumor cell invasion correlate with decrease in MMP-2/9 expression along with concomitant increase in TIMP-3 in tumor cells. Based on our exciting preliminary results we hypothesize that GTP/EGCG-mediated re-expression of TIMP-3 is a critical mechanism wherein GTP/EGCG inhibits acquisition of invasiveness by prostate cancer cells and prevents tumor metastasis. TIMP-3 directly binds to the catalytic domain of matrix metalloproteinase (MMP-2 and -9) in 1:1 stoichiometry, which are key enzymes involved in the dissolution of basement membrane. Low level of TIMP-3 protein expression has been shown to be associated with an aggressive tumor phenotype and poor disease-free survival. Under the proposed specific aim 1 we will elucidate the molecular mechanism(s) by which GTP/EGCG upregulates TIMP-3 and suppress invasiveness in prostate cancer cells. Through experiments outlined in specific aim 2, we plan to determine the in vivo effects of GTP/EGCG in upregulating TIMP-3 and preventing metastasis in preclinical models. The hypothesis is that in vivo supplementation of GTP/EGCG could effectively increase TIMP-3 expression through global modification in histone proteins and specific alterations at the TIMP-3 promoter significantly reduces metastatic incidence in pre-clinical models. We plan to use an orthotopic implantation tumor model in castrated nu/nu mice which forms primary tumor in the organ and metastasizes to the bone and an intracardiac model of tumor metastasis using SCID mice which home tumors to various soft tissue. These studies will provide mechanistic basis and novel biomarkers for clinical investigation of GTP/EGCG in the prevention of metastasis at early stages thereby reducing the mortality and increase survivorship in prostate cancer patients suffering with recurrent form of the disease.

描述（由适用提供）：该提案的总体目标是了解绿茶多酚及其主要构成（ - ） - epigallocatechin-3-gallate抑制前列腺癌转移的机制。绿茶多酚（GTP）的消费在发育方面有效，并可能在首先延迟前列腺癌的进展。然而，绿茶多酚及其主要构成的分子机制，Epigallocatechin-3-Gallate（EGCG）抑制转移过程尚未完全了解。转移是一个复杂的多步骤过程，涉及通过诱导蛋白水解酶的降解细胞外基质。基质金属蛋白酶（MMP）及其结合伴侣组织抑制剂金属蛋白酶（TIMP）的下调对于侵袭和传播恶性细胞至关重要。我们的初步研究表明，GTP/EGCG介导的肿瘤细胞浸润与MMP-2/9表达的降低以及肿瘤细胞中TIMP-3的增加相关。基于我们令人兴奋的初步结果，我们假设GTP/EGCG介导的TIMP-3的重新表达是一种关键机制，其中GTP/EGCG抑制了前列腺癌细胞对侵袭性的获取并预防肿瘤转移。 TIMP-3直接与1：1石化的基质金属蛋白酶（MMP-2和-9）的催化域结合，它们是参与基底膜溶解的关键酶。 TIMP-3蛋白表达的低水平已被证明与侵袭性肿瘤表型和无病生存率差有关。在提出的特定目的1下，我们将阐明GTP/EGCG上调TIMP-3并抑制前列腺癌细胞中的侵入性的分子机制。通过特定目标2中概述的实验，我们计划确定GTP/EGCG在上调TIMP-3中的体内效应，并防止临床前模型中的转移。假设是，GTP/EGCG的体内补充可以通过组蛋白中的全球修饰和TIMP-3启动子的特定变化有效地增加TIMP-3表达，从而显着降低了临床前模型中的转移性入射。我们计划在cast割的NU/NU小鼠中使用原位植入肿瘤模型，该肿瘤模型在器官中形成原发性肿瘤，并使用SCID小鼠转移到骨骼和肿瘤内转移的心脏内模型，这些小鼠使用将其放置在各种软组织中。这些研究将提供机械基础和新型生物标志物，以在预防早期阶段的转移中对GTP/EGCG进行临床研究，从而降低了患有这种疾病复发形式的前列腺癌患者的死亡率并增加了生存率。