The cyclooxygenase inhibitor indomethacin modulates gene expression and represses the extracellular matrix protein laminin γ1 in human glioblastoma cells

Abstract

The induction of cyclooxygenase-2 (COX-2) expression is associated with more aggressive gliomas and poor survival. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit COX activity and have antitumorigenic properties. In this report, our initial aim was to determine if indomethacin would alter gene expression as measured by suppression subtractive hybridization (SSH). Three up-regulated and four down-regulated genes by indomethacin treatment were identified. Laminin gamma1, an extracellular matrix molecule, was the most significantly repressed gene. The repression of laminin gamma1 by indomethacin was confirmed by Northern and Western blot analyses and occurred in a concentration- and time-dependent manner at the protein level. Among several NSAIDs tested, only sulindac sulfide and indomethacin suppressed laminin gamma1 protein expression, and this repression was observed in both COX-expressing and -deficient cell lines, suggesting that laminin gamma1 repression by COX inhibitors was independent of COX. Indomethacin, at a concentration that represses laminin gamma1, inhibited glioblastoma cell invasion that was partially restored with additional human laminin protein containing gamma1 chain. The repression of laminin gamma1 by NSAIDs may be related to attenuation of invasion of brain tumors. These findings are important in understanding the chemopreventive activity of some NSAIDs and could be relevant for designing therapeutic strategies against glioblastoma.

Nonsteroidal Anti-inflammatory Drugs Suppress Glioma via 15-Hydroxyprostaglandin Dehydrogenase

“…The mechanisms involved in NSAID-induced growth inhibition in GBM are not fully elucidated. For example, growth inhibitory activity of the COX inhibitor indomethacin was observed in COX-deficient GBM cells (25), and COX-2 inhibition was found to be neither necessary nor sufficient for the growth inhibitory activity of the COX-2 inhibitor celecoxib in GBM cells (26). In this study, we investigated the growth inhibitory activity of NSAIDs on GBM cells and found it to be partially COX-2-independent.…”

Induction of Cyclooxygenase-2 Expression by Interleukin-1.BETA. in Human Glioma Cell Line, U87MG

“…1) Inhibition of cyclooxygenase suppresses growth in glioma cells. 4,11,12) These non-steroidal anti-inflammatory drugs target COX and its metabolites of unsaturated fatty acids, among other target molecules, so act at the post-translational level of COX-2 in glioma cells.…”

A Review on Controversies about the Role of Immune and Inflammatory Systems in Implantation Process and Durability of Pregnancy

“…Since in the word of Longman's Embryology, L-selectin is responsible for primary adhesion of blastocyste to endometrium (52) and on the other hand non-steroid anti-inflammatory drugs (NSAID) in general and aspirin in particular can inhibit L-selectin (53), aspirin administration even at early implantation might be against logic. The other extra-cellular molecules such as Laminin (54) and Fibronectin in the word of Longman are involved in the adhesion (52), in which aspirin is respectively non effective on the first one (55) and inhibitor of the second one (56). "Laminin receptor 1" may also have an important role in human reproduction.…”

“…Its decreased expression has also been linked to shallow trophoblastic invasion which may lead to pre-eclampsia (54,57,58). Of course such molecules have variety of kinds and the mentioned references (53,55,56) are not merely related to endometrium and it's upon us to study further. Also L-selectin is abundant on cell surface of CD56 bright NKs (19); so inhibiting these NKs as a therapeutic protocol by aspirin needs to be investigated further.…”