Blockade of Tumor Growth Due to Matrix Metalloproteinase-9 Inhibition Is Mediated by Sequential Activation of β1-Integrin, ERK, and NF-κB
| Autor: | Praveen Bhoopathi, Jasti S. Rao, Sateesh Kunigal, Sajani S. Lakka, Sravan K. Vanamala, Chandramu Chetty |
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| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Small interfering RNA MAP Kinase Signaling System Matrix metalloproteinase inhibitor Apoptosis Matrix Metalloproteinase Inhibitors Transfection Models Biological Biochemistry Adenoviridae Mice chemistry.chemical_compound Cell Line Tumor Neoplasms Animals Humans Electrophoretic mobility shift assay Propidium iodide Phosphorylation Withdrawals/Retractions Extracellular Signal-Regulated MAP Kinases Molecular Biology Cell Proliferation Genes Dominant biology Integrin beta1 Cytochrome c NF-kappa B Cell Biology Molecular biology Enzyme Activation chemistry biology.protein I-kappa B Proteins Protein Processing Post-Translational Medulloblastoma |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m707931200 |
| Popis: | We previously showed that matrix metalloproteinase (MMP)-9 inhibition using an adenovirus-mediated delivery of MMP-9 small interfering RNA (Ad-MMP-9), caused senescence in medulloblastoma cells. Regardless of whether or not Ad-MMP-9 would induce apoptosis, the possible signaling mechanism is still obscure. In this report, we demonstrate that Ad-MMP-9 induced apoptosis in DAOY cells as determined by propidium iodide and terminal deoxynucleotidyltransferase-mediated nick end labeling staining. Ad-MMP-9 infection induced the release of cytochrome c, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase. Ad-MMP-9 infection stimulated ERK, and electrophoretic mobility shift assay indicated an increase in NF-kappaB activation. ERK inhibition, using a kinase-dead mutant for ERK, ameliorated NF-kappaB activation and caspase-mediated apoptosis in Ad-MMP-9-infected cells. beta1-Integrin expression in Ad-MMP-9-infected cells also increased, and this increase was reversed by the reintroduction of MMP-9. We found that the addition of beta1 blocking antibodies inhibited Ad-MMP-9-induced ERK activation. Taken together, our results indicate that MMP-9 inhibition induces apoptosis due to altered beta1-integrin expression in medulloblastoma. In addition, ERK activation plays an active role in this process and functions upstream of NF-kappaB activation to initiate the apoptotic signal. |
| Databáze: | OpenAIRE |
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