Prevention of Metastasis by Green Tea Polyphenols

绿茶多酚预防转移

• 批准号: 8887104
• 负责人: SANJAY GUPTA
• 金额: $ 7.93万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-04 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887104
• 关键词: Acetylation; Antineoplastic Agents; Basement membrane; Binding; Breast cancer metastasis; Cancer Patient; Catalytic Domain; Cause of Death; Cell Culture Techniques; Clinical Trials; Colon Carcinoma; Complex; Consumption; Data; Deacetylation; Disease-Free Survival; Distant; Dose; Down-Regulation; Enzymes; Epigallocatechin Gallate; Epigenetic Process; Gelatinase A; Genetic; Green tea; Health; Hepatocyte Growth Factor; Histone Deacetylase Inhibitor; Histones; Human; In Vitro; Incidence; Invaded; Kidney; Liver; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of prostate; Matrix Metalloproteinases; Mediating; Medical; Modeling; Modification; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Oral; Organ; Phenotype; Polycomb; Pre-Clinical Model; Prevention; Primary Neoplasm; Process; Prostate; Prostatic Neoplasms; Protein Subunits; Proteins; Publishing; Repression; Risk; Role; Site; Staging; Supplementation; Tissue Inhibitor of Metalloproteinase-3; Tissues; Transgenic Mice; Trichostatin A; Tumor Angiogenesis; Tumor Cell Invasion; Tumor Suppressor Proteins; Vascular Endothelial Growth Factors; Work; base; bone; cancer cell; cost effective; drinking; gallocatechol; histone methylation; histone modification; human EZH2 protein; implantation; improved; in vivo; inhibitor/antagonist; lymph nodes; metastasis prevention; metastatic process; mortality; mouse model; neoplastic cell; novel; novel strategies; prevent; promoter; prostate cancer cell; prostate cancer model; protein expression; stoichiometry; survivorship; transgenic adenocarcinoma of mouse prostate; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Green tea polyphenols (GTP) and its major constituent, epigallocatechin-3-gallate (EGCG) has been associated with reduced risk of prostate cancer progression and emerged as a promising suppressor of metastasis. Our published study (Gupta et al. Proc. Natl. Acad. Sci. USA 98:10350-5, 2001) has shown that oral consumption of green tea polyphenols by transgenic mice [the TRAMP mouse model (transgenic adenocarcinoma of the mouse prostate)] genetically predisposed to developing prostate cancer, at doses readily achievable in humans, results in significant inhibition of primary tumor and completely prevented metastases to distant-site organs. Nonetheless, the mechanism of action of green tea polyphenols in blocking the metastatic process in cancer cells remains largely unknown. Based on the results of our preliminary studies we hypothesize that GTP/EGCG-mediated re-expression of Tissue Inhibitor of Metalloproteinases (TIMP)-3 is a critical mechanism wherein GTP/EGCG inhibits invasion of prostate cancer cells thereby preventing 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 associated with an aggressive tumor phenotype and poor disease-free survival. Under the proposed specific aim 1 we will investigate the epigenetic mechanism(s) by which GTP/EGCG reactivates TIMP-3 and suppress invasiveness in prostate cancer cells. Specific aim 2 will determine the in vivo effects of GTP/EGCG in reactivating TIMP-3 and preventing metastasis. 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 reducing metastatic cascade in pre-clinical model. We plan to use an orthotopic implantation of C4-2B tumor cells in castrated nu/nu mice which forms primary tumor in the organ and metastasizes to the bone and invades local tissue including lymph nodes and liver. These studies will provide mechanistic basis of understanding the effect of GTP/EGCG in the prevention of prostate cancer metastasis.

描述（由申请人提供）：绿茶多酚（GTP）及其主要成分表没食子儿茶素-3-没食子酸酯（EGCG）与降低前列腺癌进展风险相关，并成为一种有前景的转移抑制剂。我们发表的研究（Gupta 等人 Proc. Natl. Acad. Sci. USA 98:10350-5, 2001）表明，转基因小鼠 [TRAMP 小鼠模型（小鼠前列腺转基因腺癌​​）] 口服绿茶多酚在遗传上易患前列腺癌，在人类容易达到的剂量下，可显着抑制原发肿瘤和 完全阻止了远处器官的转移。尽管如此，绿茶多酚阻断癌细胞转移过程的作用机制仍然很大程度上未知。根据我们的初步研究结果，我们假设 GTP/EGCG 介导的金属蛋白酶组织抑制剂 (TIMP)-3 的重新表达是 GTP/EGCG 抑制前列腺癌细胞侵袭从而预防肿瘤转移的关键机制。 TIMP-3以1:1化学计量直接与基质金属蛋白酶（MMP-2和-9）的催化结构域结合，这是参与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率相关。根据提出的具体目标 1，我们将研究 GTP/EGCG 重新激活 TIMP-3 并抑制前列腺癌细胞侵袭的表观遗传机制。具体目标 2 将确定 GTP/EGCG 在重新激活 TIMP-3 和预防转移方面的体内作用。假设体内补充 GTP/EGCG 可以通过组蛋白的整体修饰和 TIMP-3 启动子的特异性改变有效增加 TIMP-3 的表达，从而显着减少临床前模型中的转移级联。我们计划在去势的 nu/nu 小鼠中原位植入 C4-2B 肿瘤细胞，在器官中形成原发肿瘤，并转移至骨骼并侵入局部组织，包括淋巴结和肝脏。这些研究将为理解GTP/EGCG在预防前列腺癌转移中的作用提供机制基础。