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J. Biol. Chem., Vol. 283, Issue 3, 1545-1552, January 18, 2008

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Blockade of Tumor Growth Due to Matrix Metalloproteinase-9 Inhibition Is Mediated by Sequential Activation of β1-Integrin, ERK, and NF-B^*

Praveen Bhoopathi, Chandramu Chetty, Sateesh Kunigal, Sravan K. Vanamala, Jasti S. Rao, and Sajani S. Lakka¹

From the Program of Cancer Biology, Department of Cancer Biology and Pharmacology, and the Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, Illinois 61605

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-B activation. ERK inhibition, using a kinase-dead mutant for ERK, ameliorated NF-B activation and caspase-mediated apoptosis in Ad-MMP-9-infected cells. β1-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 β1 blocking antibodies inhibited Ad-MMP-9-induced ERK activation. Taken together, our results indicate that MMP-9 inhibition induces apoptosis due to altered β1-integrin expression in medulloblastoma. In addition, ERK activation plays an active role in this process and functions upstream of NF-B activation to initiate the apoptotic signal.

Received for publication, September 21, 2007 , and in revised form, November 6, 2007.

^* This research was supported by NCI, National Institutes of Health, Grant CA 75557, CA 92393, CA 95058, CA 116708, NINDS NS 47699, and NS 57529, Caterpillar, Inc., and OSF St. Francis, Inc. (Peoria, IL) (to J. S. R.) and a Children's Miracle Network grant (to S. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cancer Biology and Pharmacology, University of Illinois College of Medicine, One Illini Dr., Peoria, IL 61605. Tel.: 309-671-3445; Fax: 309-671-3442; E-mail: slakka{at}uic.edu.

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