Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 3, Pages 1545-1552Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M707931200
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Funding
- NCI NIH HHS [CA 95058, R01 CA095058, R01 CA095058-04, CA 75557, R01 CA092393-04, R01 CA075557-09, CA 116708, R01 CA092393, R01 CA116708-02, R01 CA075557, R01 CA116708, CA 92393] Funding Source: Medline
- NINDS NIH HHS [NS 57529, R01 NS047699-03, R01 NS047699, R01 NS057529, NS 47699, R01 NS057529-01] Funding Source: Medline
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We previously showed that matrix metalloproteinase (MMP)-9 inhibition using an adenovirus-mediated delivery of MMP-9small 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-kappa B activation. ERK inhibition, using a kinase- dead mutant for ERK, ameliorated NF-kappa B activation and caspase- mediated apoptosis in Ad-MMP-9-infected cells. beta 1-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 beta 1 blocking antibodies inhibited Ad-MMP-9-induced ERK activation. Taken together, our results indicate that MMP-9 inhibition induces apoptosis due to altered beta 1-integrin expression in medulloblastoma. In addition, ERK activation plays an active role in this process and functions upstream of NF-kappa B activation to initiate the apoptotic signal.
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