MMP-9 Short Interfering RNA Induced Senescence Resulting in Inhibition of Medulloblastoma Growth Via P16(INK4a) and Mitogen-activated Protein Kinase Pathway

Overview

Journal Cancer Res

Specialty Oncology

Date 2007 May 19

PMID 17510426

Citations 27

Authors

Jasti S Rao

Praveen Bhoopathi

Chandramu Chetty

Meena Gujrati

Sajani S Lakka

Affiliations

Soon will be listed here.

Abstract

The involvement of matrix metalloproteinases (MMP) has been suggested in cellular mechanisms leading to medulloblastoma, the most common malignant brain tumor in children. A significant association of the expression levels of MMP-9 with survival and M stage suggests that patients with medulloblastoma metastatic disease at diagnosis may benefit from the anti-MMP therapy. Here, we have evaluated the tumorigenicity of medulloblastoma cells after infection with an adenovirus containing a 21-bp short interfering RNA sequence of the human MMP-9 gene (Ad-MMP-9). Infection of Daoy medulloblastoma cells with Ad-MMP-9 reduced MMP-9 activity and protein levels compared with parental and Ad-SV controls. Ad-MMP-9 decreased the number of viable Daoy cells in a concentration-dependent manner. Fluorescence-activated cell sorting analysis indicated that Ad-MMP-9 infection caused a dose-dependent cell cycle arrest in the G(0)-G(1) phase. Ad-MMP-9-induced cell cycle arrest seems to be mediated by the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway and the cell cycle inhibitor p16(INK4a) and is phenotypically indistinguishable from senescence. Ad-MMP-9 treatment inhibited medulloblastoma tumor growth in an intracranial model and was mediated by up-regulation of p16 expression. These studies validate the usefulness of targeting MMP-9 and provide a novel perspective in the treatment of medulloblastoma.

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