Research

A MT1-MMP/NF-κB signaling axis as a checkpoint controller of COX-2 expression in CD133(+) U87 glioblastoma cells

Borhane Annabi^1* , Carl Laflamme^1* , Asmaa Sina¹ , Marie-Paule Lachambre² and Richard Béliveau²

¹  Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre de Recherche BIOMED, Université du Québec à Montréal, Quebec, Canada

²  Laboratoire de Médecine Moléculaire, Department of Neurosurgery, CHUM and UQAM, Montreal, Quebec, Canada

author email corresponding author email* Contributed equally

Journal of Neuroinflammation 2009, 6:8doi:10.1186/1742-2094-6-8

Published:	9 March 2009

Abstract

Background

The CD133(+) stem cell population in recurrent gliomas is associated with clinical features such as therapy resistance, blood-brain barrier disruption and, hence, tumor infiltration. Screening of a large panel of glioma samples increasing histological grade demonstrated frequencies of CD133(+) cells which correlated with high expression of cyclooxygenase (COX)-2 and of membrane type-1 matrix metalloproteinase (MT1-MMP).

Methods

We used qRT-PCR and immunoblotting to examine the molecular interplay between MT1-MMP and COX-2 gene and protein expression in parental, CD133(+), and neurospheres U87 glioma cell cultures.

Results

We found that CD133, COX-2 and MT1-MMP expression were enhanced when glioma cells were cultured in neurosphere conditions. A CD133(+)-enriched U87 glioma cell population, isolated from parental U87 cells with magnetic cell sorting technology, also grew as neurospheres and showed enhanced COX-2 expression. MT1-MMP gene silencing antagonized COX-2 expression in neurospheres, while overexpression of recombinant MT1-MMP directly triggered COX-2 expression in U87 cells independent from MT1-MMP's catalytic function. COX-2 induction by MT1-MMP was also validated in wild-type and in NF-κB p65^-/- mutant mouse embryonic fibroblasts, but was abrogated in NF-κB1 (p50^-/-) mutant cells.

Conclusion

We provide evidence for enhanced COX-2 expression in CD133(+) glioma cells, and direct cell-based evidence of NF-κB-mediated COX-2 regulation by MT1-MMP. The biological significance of such checkpoint control may account for COX-2-dependent mechanisms of inflammatory balance responsible of therapy resistance phenotype of cancer stem cells.