INHIBITION OF CELL-MEDIATED PROMMP-2 ACTIVATION IN ORAL CANCER

口腔癌中细胞介导的 PROMMP-2 激活的抑制

• 批准号: 7417536
• 负责人: XIAOPING XU
• 金额: $ 7.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7417536
• 关键词: Accounting; Active Sites; Adverse effects; Area; Benign; Binding; Biochemical; Biological; Catalytic Domain; Cell Culture System; Cell membrane; Cell surface; Cells; Characteristics; Cleaved cell; Clinical; Clinical Trials; Complex; Depth; Development; Diabetes Mellitus; Endopeptidases; Enzyme Activation; Enzymes; Extracellular Matrix; Family; Family member; Figs - dietary; Gelatinase A; Goals; Hemopexin; In Vitro; Individual; Inhibition of Matrix Metalloproteinases Pathway; Lead; Libraries; Malignant - descriptor; Malignant Neoplasms; Matrilysin; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Membrane; Molecular; Neoplasm Metastasis; Pathway interactions; Peptides; Periodontal Diseases; Periodontal Infection; Physiological; Process; Rate; Recombinant Proteins; Regulation; Research; Research Project Grants; Resources; Specificity; Structure; System; Testing; Therapeutic Intervention; Time; Tissues; Tumor Expansion; United States; Wound Healing; base; cancer cell; cancer diagnosis; cell behavior; design; experience; human MMP14 protein; inhibitor/antagonist; innovation; macromolecule; malignant mouth neoplasm; novel; novel strategies; proMMP-2; research study; tool

DESCRIPTION (provided by applicant): Oral cancer is the sixth most common cancer in the world and characterized by a high degree of local invasiveness and a high rate of metastasis. High level expression and activity of MMP-2, a member of the family of matrix metalloproteinases (MMPs), has been associated with increased tumor expansion and metastasis of oral cancers. The potential utility of MMP inhibitors has therefore lead to significant research in the area. Although several currently available inhibitors are efficient on MMPs, they generally have low specificity for individual MMPs due to the structural similarity of the catalytically active sites among the MMPs. Consequently, clinical cancer trials with such inhibitors have experienced significant clinical side effects due to the non-specific MMP inhibition. While there is little regulation of MMP-2 at the transcriptional level, this enzyme is subject to a unique activation process among the MMPs. MMP-2 activation occurs in a cell membrane-associated complex involving membrane type 1 MMPs (MT1-MMPs), tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and proMMP-2. That addition of excess soluble TIMP-2 added to the activation system inhibits MMP-2 activation points to a possible novel strategy for specific MMP-2 inhibition. The hypothesis of this proposal is that peptides may be identified which block interactions in the activation complex between TIMP-2 and proMMP-2 and thereby inhibit the MMP-2 activities. The experiments are designed to use advanced recombinant protein biochemical and molecular biological approaches to identify inhibitors from random libraries of short peptides. Peptides with the appropriate binding characteristics will be synthesized and tested in vitro and in a cancer cell culture system to determine whether the peptides inhibit the MMP-2 activation and activity, and in turn alter cancer cell behavior. The proposed experiments will generate the information required to pursue the long-term goal which is to explore in detail the structure-function basis of MMP-2 activation and to develop new MMP inhibitors and strategies for use in treatment of oral cancer. Enzymes called MMPs can degrade tissues and are important for progression of oral cancer. This research project will test new approaches to inhibit MMPs. The goal is to develop MMP inhibitors for treatment of oral cancer.

描述（由申请人提供）：口腔癌是世界上第六个最常见的癌症，其特征是高度局部侵入性和高转移率。 MMP-2的高水平表达和活性是基质金属蛋白酶（MMP）家族的成员，与口服癌症的肿瘤膨胀和转移增加有关。因此，MMP抑制剂的潜在效用已导致该地区的重大研究。尽管目前有几种可用的抑制剂在MMP上有效，但由于MMP中催化活性位点的结构相似性，它们通常对单个MMP的特异性较低。因此，由于非特异性MMP抑制作用，具有此类抑制剂的临床癌症试验具有显着的临床副作用。尽管在转录级别几乎没有MMP-2的调节，但该酶在MMP中受到独特的激活过程。 MMP-2激活发生在涉及1型膜1 MMP（MT1-MMP），基质金属蛋白酶-2（TIMP-2）和ProMMP-2的组织抑制剂的细胞膜相关复合物中。多余的可溶性TIMP-2添加到激活系统中抑制了MMP-2激活指向特定MMP-2抑制的新型策略。该提议的假设是可以确定肽可以阻止TIMP-2和Prommp-2之间的激活复合物中的相互作用，从而抑制MMP-2活性。该实验旨在使用晚期重组蛋白生化和分子生物学方法来鉴定短肽随机文库的抑制剂。具有适当结合特性的肽将在体外和癌细胞培养系统中合成和测试，以确定肽是否抑制MMP-2激活和活性，进而改变癌细胞的行为。提出的实验将生成追求长期目标所需的信息，该目标是详细探讨MMP-2激活的结构功能基础，并开发新的MMP抑制剂和用于治疗口腔癌的策略。称为MMP的酶可以降解组织，对于口腔癌进展至关重要。该研究项目将测试抑制MMP的新方法。目的是开发用于治疗口腔癌的MMP抑制剂。