Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro

Abstract

Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.

Up-Regulation of Cyclooxygenase-2 (COX-2) Expression by Temozolomide (TMZ) in Human Glioblastoma (GBM) Cell Lines

“…Our findings also show that NS398 was able to overcome TMZ-induced overexpression of β-catenin, MGMT, and SOX-2 in T98G, thus confirming the key and the hierarchically superior role played by the COX-2/PGE2 system in the cascade of pathways activated by TMZ and implicated in chemoresistance. NS398 has been one of the earliest COX-2-selective inhibitors discovered [54] and, even if not yet approved by the FDA for clinical use, it continues to be largely used, also recently, by a plethora of researchers, as a prototype COX-2 inhibitor for in vitro and in vivo studies on several types of cancers, including GBM [20,36,55,56]. For our group, in particular, the present work represents a continuation of previous studies showing the ability of NS398 to influence the biology of GBM cell lines as well as the relative derived-neurospheres [13].…”

“…The sulphonamide derivative NS398 is a highly selective COX-2 inhibitor, and even if not yet approved by the Food and Drug Administration (FDA) for clinical use, several studies have reported effective activity on glioma cell lines [20,21]. NS398 has been reported to significantly reduce the proliferation and migration rate and alter the cell cycle phase distribution of GBM cell lines [20,36].…”

Effect of Polyunsaturated Fatty Acids on Temozolomide Drug-Sensitive and Drug-Resistant Glioblastoma Cells

“…Cell cycle phase was determined by propidium iodide fluorescence detection of 10,000 events in a Guava ® easyCyte flow cytometer (Millipore, Burlington, MA, USA) using a λ ext. of 532 nm for propidium iodide detection [ 41 , 42 ].…”

Biosynthesis and Significance of Fatty Acids, Glycerophospholipids, and Triacylglycerol in the Processes of Glioblastoma Tumorigenesis

“…The most important products of COX-2 activity in cancer processes are prostaglandin E 2 (PGE 2 ) [ 59 ] and prostaglandin E 3 (PGE 3 ) [ 60 ], which are derived from ARA 20:4n-6 and EPA C20:5n-3, respectively. PGE 2 is important in the development of glioblastoma tumors [ 61 , 62 , 63 ] and is associated with radiation resistance [ 62 , 64 ] and TMZ resistance in glioblastoma [ 65 ]. On the other hand, PGE 3 acts as an antitumor agent by reducing the activity of PGE 2 [ 60 ].…”