title: Ensnaring membrane type 1-matrix metalloproteinase (MT1-MMP) with tissue inhibitor of metalloproteinase (TIMP)-2 using the haemopexin domain of the protease as a carrier: a targeted approach in cancer inhibition.
abstract: Metastatic cancer cells express Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) to degrade the extracellular matrix in order to facilitate migration and proliferation. Tissue Inhibitor of Metalloproteinase (TIMP)-2 is the endogenous inhibitor of the MMP. Here, we describe a novel and highly effective fusion strategy to enhance the delivery of TIMP-2 to MT1-MMP. We can reveal that TIMP-2 fused to the haemopexin +/- transmembrane domains of MT1-MMP (two chimeras named T2PEX+TM and T2PEX) are able to interact with MT1-MMP on the cell surface as well as intracellularly. In the case of T2PEX+TM, there is even a clear sign of MT1-MMP:T2PEX+TM aggregation by the side of the nucleus to form aggresomes. In vitro, T2PEX+TM and T2PEX suppress the gelatinolytic and invasive abilities of cervical carcinoma (HeLa) and HT1080 fibrosarcoma cancer cells significantly better than wild type TIMP-2. In mouse xenograft, we further demonstrate that T2PEX diminishes cervical carcinoma growth by 85% relative to the control. Collectively, our findings indicate the effectiveness of the fusion strategy as a potential targeted approach in cancer inhibition.
authors.affiliation: Department of Biological Sciences, Xian Jiaotong Liverpool University, Suzhou 215123, China.
authors.forename: Bingjie
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Biological Sciences, Xian Jiaotong Liverpool University, Suzhou 215123, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, Xian Jiaotong Liverpool University, Suzhou 215123, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biological Sciences, Xian Jiaotong Liverpool University, Suzhou 215123, China.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Tsigkou
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, United Kingdom.
authors.forename: Magdalini
authors.initials: M
authors.lastname: Rapti
authors.affiliation: Department of Biological Sciences, Xian Jiaotong Liverpool University, Suzhou 215123, China.
authors.forename: Meng Huee
authors.initials: MH
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006466:Hemopexin / Q000737:chemistry*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D061965:Matrix Metalloproteinase Inhibitors; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D006466:Hemopexin; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: MT1-MMP; TIMP; cancer; haemopexin; protein engineering