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Nucleic acid-induced potentiation of matrix metalloproteinase-9 enzymatic activity.

ABSTRACT: Matrix metalloproteinases (MMPs) play varied roles in normal biology and diseases where, depending on the context, both inhibition and enhancement of the enzymatic activity may be beneficial. However, there are very few reports of positive modulators of MMP activity. We report that polynucleotides, including single-stranded DNA, RNA, and even double-stranded DNA, bind to and enhance the enzymatic activity of MMP9. This enhancement of MMP9 catalytic activity is not shared by biologically active polycationic molecules suggesting nonspecific charge screening as an unlikely mechanism. Deletion construct and MMP1, 2, and 3 studies suggest that the type-II fibronectin repeat domains of the enzyme appear to play a role in mediating the nucleotide potentiation of MMP9 activity. Single-stranded DNA enhances nerve growth factor-induced MMP9-dependent neurite extension in pheochromocytoma 12 cells providing evidence for potential biological significance of the nucleotide-mediated allosteric enhancement of the catalytic activity.

SUBMITTER: Duellman T

PROVIDER: S-EPMC5941315 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Nucleic acid-induced potentiation of matrix metalloproteinase-9 enzymatic activity.

Duellman Tyler T Chen Xi X Wakamiya Rie R Yang Jay J

The Biochemical journal 20180509 9

Matrix metalloproteinases (MMPs) play varied roles in normal biology and diseases where, depending on the context, both inhibition and enhancement of the enzymatic activity may be beneficial. However, there are very few reports of positive modulators of MMP activity. We report that polynucleotides, including single-stranded DNA, RNA, and even double-stranded DNA, bind to and enhance the enzymatic activity of MMP9. This enhancement of MMP9 catalytic activity is not shared by biologically active p ...[more]

PMID: 29654109

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Project description:BackgroundIonizing radiation (IR) in combination with microtubule stabilizing agents (MSA) is a promising combined treatment modality. Supra-additive treatment responses might result from direct tumor cell killing and cooperative indirect, tumor cell-mediated effects on the tumor microenvironment. Here we investigated deregulation of matrix metalloproteinase (MMP) activity, as an important component of the tumor microenvironment, by the combined treatment modality of IR with the clinically relevant MSA patupilone.MethodsExpression, secretion and activity of MMPs and related tissue inhibitors of metalloproteinases (TIMPs) were determined in cell extracts and conditioned media derived from human fibrosarcoma HT1080 and human glioblastoma U251 tumor cells in response to treatment with IR and the MSA patupilone. Treatment-dependent changes of the invasive capacities of these tumor cell lines were analysed using a Transwell invasion assay. Control experiments were performed using TIMP-directed siRNA and TIMP-directed inhibitory antibodies.ResultsEnzymatic activity of secreted MMPs was determined after treatment with patupilone and irradiation in the human fibrosarcoma HT1080 and the human glioblastoma U251 tumor cell line. IR enhanced the activity of secreted MMPs up to 2-fold and cellular pretreatment with low dose patupilone (0.05-0.2 nM) counteracted specifically the IR-induced MMP activity. The cell invasive capacity of HT1080 and U251 cells was increased after irradiation with 2 Gy by 30% and 50%, respectively, and patupilone treatment completely abrogated IR-induced cell invasion. Patupilone did not alter the level of MMP expression, but interestingly, the protein level of secreted TIMP-1 and TIMP-2 was lower after combined treatment than after irradiation treatment alone. Furthermore, siRNA depletion of TIMP-1 or TIMP-2 prevented IR-mediated induction of MMP activity and cell invasion.ConclusionsThese results indicate that patupilone counteracts an IR-induced MMP activation process by the reduction of secreted TIMP-1 and TIMP-2 proteins, which are required for activation of MMPs. Since IR-induced MMP activity could contribute to tumor progression, treatment combination of IR with patupilone might be of great clinical benefit for tumor therapy.

Dataset Information

Nucleic acid-induced potentiation of matrix metalloproteinase-9 enzymatic activity.

Publications

Nucleic acid-induced potentiation of matrix metalloproteinase-9 enzymatic activity.

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