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: 7034342
• 负责人: Jian Cao
• 金额: $ 27.45万
• 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/7034342
• 关键词: cadherins; cell migration; lead; neoplasm /cancer; neoplasm /cancer therapy; neoplastic cell

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-间质转化（EMT）已成为癌症早期的关键步骤。更好地理解EMT的机制将促进抑制剂的开发，以防止癌症进展。相当多的证据表明，膜型1-基质金属蛋白酶（MT 1-MMP）在EMT和转化为侵袭性癌症中起作用。MT 1-MMP激活proMMP-2和降解细胞外基质（ECM）成分参与癌症进展。MT 1-MMP还切割许多细胞表面蛋白、生长因子和趋化因子。我们最近证明，MT 1-MMP：1）在细胞-细胞粘附素连接处切割E-钙粘素; 2）促进细胞在3D I型胶原凝胶中的迁移/分散; 3）在体外和体内调节细胞增殖; 5）改变3D I型胶原凝胶中的细胞形态。我们还证明了MT 1-MMP的血液结合蛋白（PEX）结构域在癌细胞迁移中发挥着至关重要的作用，并精确定位了MT 1-MMP介导的细胞迁移所需的区域。用重组MT 1-MMP PEX蛋白靶向PEX结构域导致对MT 1-MMP诱导的细胞迁移的干扰。本申请的主要目的是确定MT 1-MMP在EMT中的催化和非催化活性的参与。这种特性将有助于我们开发MT 1-MMP的特异性非催化结构域抑制剂，用于干扰癌症进展。为了实现该目的，将检查MT 1-MMP在3D培养的癌细胞中的EMT中的功能。EMT相关的转录程序和信号通路将进行评估。基于MT 1-MMP的计算模型和与其他MMP的相似性，将使用诱变方法鉴定MT 1-MMP的PEX结构域中癌细胞迁移所需的最小基序。将确定通过PEX结构域形成MT 1-MMP的同源二聚体和/或异源寡聚体。基于关键PEX基序的鉴定，将使用分析化学和细胞生物学方法设计和表征特异性MT 1-MMP抑制肽。将在体内癌症模型中产生和评价功能性抑制肽。长期目标是开发一种先导化合物，该化合物将被修饰以产生用于治疗癌症的副作用最小的MT 1-MMP抑制药物。我建议，目前的项目将有助于我们更好地了解癌症的进展，并导致开发新的基本工具，用于治疗早期癌症。