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大常见癌症，其特征在于高度的局部侵袭性和高转移率。基质金属蛋白酶（MMP）家族成员MMP-2的高水平表达和活性与口腔癌的肿瘤扩展和转移有关。因此，MMP抑制剂的潜在效用导致了该领域的重大研究。尽管几种目前可用的抑制剂对MMP是有效的，但由于MMP之间的催化活性位点的结构相似性，它们通常对单个MMP具有低特异性。因此，由于非特异性MMP抑制，使用此类抑制剂的临床癌症试验经历了显著的临床副作用。虽然MMP-2在转录水平上几乎没有调节，但这种酶在MMP中经历独特的活化过程。MMP-2活化发生在涉及膜1型MMP（MT 1-MMP）、基质金属蛋白酶组织抑制剂-2（TIMP-2）和proMMP-2的细胞膜相关复合物中。将过量的可溶性TIMP-2添加到活化系统中抑制MMP-2活化，这表明特异性MMP-2抑制的可能的新策略。该建议的假设是，可以鉴定出阻断TIMP-2和proMMP-2之间的活化复合物中的相互作用从而抑制MMP-2活性的肽。这些实验旨在使用先进的重组蛋白生化和分子生物学方法从随机短肽库中鉴定抑制剂。将合成具有适当结合特性的肽，并在体外和癌细胞培养系统中进行测试，以确定肽是否抑制MMP-2活化和活性，并进而改变癌细胞行为。拟议的实验将产生追求长期目标所需的信息，这是详细探索MMP-2激活的结构-功能基础，并开发新的MMP抑制剂和策略用于治疗口腔癌。被称为MMPs的酶可以降解组织，对口腔癌的进展很重要。该研究项目将测试抑制MMPs的新方法。目标是开发用于治疗口腔癌的MMP抑制剂。