Targeting the PEX Domain of MT1-MMP: Novel Cancer Therapy

靶向 MT1-MMP 的 PEX 结构域：新型癌症疗法

• 批准号: 7201583
• 负责人: Jian Cao
• 金额: $ 26.71万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201583
• 关键词: 3-Dimensional; Adverse effects; Analytical Chemistry; Award; Base Sequence; Basement membrane; Behavior; Biological; Blood; Blood Vessels; CD44 Antigens; Cancer Model; Cancer Research Project; Carcinoma; Carcinoma in Situ; Catalytic Domain; Cell Adhesion Molecules; Cell Nucleus; Cell Proliferation; Cell Surface Proteins; Cell surface; Cell-Cell Adhesion; Cells; Cellular Morphology; Class; Cleaved cell; Collagen Type I; Complex; Computer Simulation; Data; Development; Diagnostic Neoplasm Staging; Dissection; Doctor of Medicine; E-Cadherin; Early treatment; Epithelial; Experimental Models; Extracellular Matrix; Extracellular Matrix Degradation; Figs - dietary; Fostering; Gel; Gene Expression Profile; Genetic Transcription; Goals; Growth; Hemopexin; In Situ; In Vitro; Interstitial Collagenase; Invasive; Lead; Loss of E-cadherin Expression; Lymph; Malignant Neoplasms; Malignant neoplasm of prostate; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mesenchymal; Modeling; Mutagenesis; Neoplasm Metastasis; PHEX protein; Peptides; Pharmaceutical Preparations; Play; Process; Property; Prostatic Neoplasms; Protein Overexpression; Recombinant DNA; Recombinants; Research Personnel; Role; Safety; Signal Pathway; Specificity; Staging; Techniques; Tumor Cell Invasion; Tumor stage; base; cancer cell; cancer therapy; cell motility; chemokine; design; drug development; drug discovery; epithelial to mesenchymal transition; human MMP14 protein; in vivo; in vivo Model; inhibitor/antagonist; neoplastic cell; novel; prevent; proMMP-2; programs; three dimensional structure; tool; tumor progression

DESCRIPTION (provided by applicant): Epithelial-to-mesenchymal transition (EMT) has emerged as a critical step in the early stage of cancer. Better understanding of the mechanism of EMT will foster the development of inhibitors to prevent cancer progression. Considerable evidence has implicated membrane type 1-matrix metalloproteinase (MT1-MMP) in EMT and conversion to aggressive cancers. MT1-MMP activation of proMMP-2 and degradation of extracellular matrix (ECM) components are involved in cancer progression. MT1-MMP also cleaves numerous cell surface proteins, growth factors, and chemokines. We recently demonstrated that MT1-MMP: 1) cleaves E-cadherin at the cell-cell adherins junctions; 2) promotes cell migration/scattering in 3D type I collagen gels; 3) regulates cell proliferation in vitro and in vivo; and 5) changes cell morphology in 3D type I collagen gels. We also demonstrated that the hemopexin (PEX) domain of MT1-MMP plays a crucial role in cancer cell migration and pinpointed the regions required for MT1-MMP-mediated cell migration. Targeting the PEX domain with recombinant MT1-MMP PEX protein resulted in interference with MT1-MMP-induced cell migration. The primary goal of this application is to define the involvement of the catalytic and non-catalytic activities of MT1 -MMP in EMT. This characterization will facilitate our development of specific non-catalytic domain inhibitors of MT1-MMP that will be employed to interfere with cancer progression. To achieve this aim, the function of MT1-MMP in EMT in 3D cultured cancer cells will be examined. EMT-related transcription programs and signaling pathways will be evaluated. Based on a computational model of MT1-MMP and similarity with other MMPs, minimum motif(s) in the PEX domain of MT1-MMP required for cancer cell migration will be identified using a mutagenesis approach. Formation of homodimer and/or heterooligomer of MT1-MMP through PEX domain will be determined. Based on the identification of crucial PEX motifs, specific MT1-MMP inhibitory peptides will be designed and characterized using analytical chemistry and cell biological approaches. Functional inhibitory peptides will be produced and evaluated in an in vivo cancer model. The long-term goal is to develop a lead compound that will be modified to produce an MT1-MMP inhibitory drug with minimal side effects for treatment of cancer. I propose that the current project will help us to better understand cancer progression and lead to the development of novel basic tools for treatment of early stage cancer.

描述(由申请人提供)：上皮向间充质转化(EMT)已成为癌症早期的关键步骤。更好地了解EMT的机制将促进抑制物的开发以防止癌症进展。大量证据表明，膜型1-基质金属蛋白酶(MT1-MMPs)参与了EMT和向侵袭性癌症的转化。MT1-MMPProMMP2的激活和细胞外基质(ECM)成分的降解参与了肿瘤的进展。MT1-基质金属蛋白酶还能裂解许多细胞表面蛋白、生长因子和趋化因子。我们最近证实MT1-MMP1：1)在细胞-细胞粘附素连接处裂解E-钙粘蛋白；2)促进细胞在3DI型胶原凝胶中的迁移/分散；3)调节细胞在体外和体内的增殖；以及5)改变3DI型胶原凝胶中的细胞形态。我们还证明了MT1-基质金属蛋白酶的血凝蛋白(PEX)结构域在癌细胞迁移中起着关键作用，并精确定位了MT1-基质金属蛋白酶介导的细胞迁移所需的区域。重组MT1-MMPPEX蛋白靶向PEX结构域可干扰MT1-MMPPEX蛋白诱导的细胞迁移。本应用的主要目的是确定MT1-MMPs的催化和非催化活性在EMT中的作用。这一特征将有助于我们开发特定的MT1-基质金属蛋白酶非催化结构域抑制物，用于干扰癌症进展。为了达到这一目的，将检测MT1-MMP3维培养癌细胞EMT中MT1-MMPs的功能。与EMT相关的转录程序和信号通路将被评估。基于MT1-MMPs的计算模型和与其他MMPs的相似性，将使用突变方法确定Mt1-MMPPEx结构域中癌细胞迁移所需的最小基序(S)。将确定通过PEX结构域形成MT1-基质金属蛋白酶的同二聚体和/或异寡体。在确定关键的PEX基序的基础上，将利用分析化学和细胞生物学方法设计和表征特定的MT1-基质金属蛋白酶抑制肽。功能抑制肽将在体内癌症模型中生产和评估。长期目标是开发一种先导化合物，这种化合物将经过修饰，产生一种副作用最小的MT1-MMP抑制药物，用于癌症治疗。我认为，目前的项目将帮助我们更好地了解癌症的进展，并导致开发治疗早期癌症的新的基本工具。