TIMP3: A Molecular Target of Green Tea Polyphenols

TIMP3：绿茶多酚的分子靶点

• 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
• 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

 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(申请人提供)：本提案的总体目标是了解绿茶多酚及其主要成分(-)-表没食子儿茶素没食子酸酯抑制前列腺癌转移的机制。食用绿茶多酚(GTP)在前列腺癌的发育过程中是有效的，并可能在一开始就延缓前列腺癌的进展。然而，绿茶多酚及其主要成分表没食子儿茶素没食子酸酯(EGCG)抑制肿瘤转移的分子机制(S)尚不完全清楚。转移是一个复杂的多步骤过程，涉及到通过诱导蛋白水解酶来降解细胞外基质。基质金属蛋白酶(MMPs)及其结合伴侣金属蛋白酶组织抑制因子(TIMPs)的下调对恶性细胞的侵袭和扩散至关重要。我们的初步研究表明，GTP/EGCG介导的肿瘤细胞侵袭与肿瘤细胞中MMP-2/9的表达减少以及TIMP-3的表达增加相关。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GTP/EGCG抑制前列腺癌细胞侵袭和防止肿瘤转移的关键机制。TIMP-3以1：1的化学计量比直接与基质金属蛋白酶的催化结构域(基质金属蛋白酶-2和-9)结合，这两种酶是基底膜溶解的关键酶。低水平的TIMP-3蛋白表达与侵袭性肿瘤表型和较差的无病生存期有关。在所提出的特异性目标1下，我们将阐明GTP/EGCG上调TIMP-3和抑制前列腺癌侵袭力的分子机制(S)。通过特定目标2中概述的实验，我们计划在临床前模型中确定GTP/EGCG在上调TIMP-3和防止转移方面的体内效应。假设在体内补充GTP/EGCG可以通过组蛋白的全局修饰有效地增加TIMP-3的表达，并且在临床前模型中TIMP-3启动子的特异性改变显著降低转移发生率。我们计划在去势的nu/nu小鼠身上使用原位移植肿瘤模型，该模型在器官中形成原发肿瘤并转移到骨骼，并使用将肿瘤寄生到各种软组织的SCID小鼠来建立心脏内肿瘤转移模型。这些研究将为GTP/EGCG预防前列腺癌早期转移的临床研究提供机制基础和新的生物标志物，从而降低前列腺癌复发患者的死亡率，提高患者的生存率。