Fig. 10

COXIBs and 2,5-DMC counteract the hyperactivated Wnt/β-catenin pathway and COX-2/PGE2/EP4 signaling in glioblastoma cells. Arachidonic acid (AA) is released from cell membrane via the action of phospholipase A2 (PLA2) and converted to prostaglandin H2 (PGH2) through the activity of COX-2 enzyme. PGH2 is further transformed to five types of prostanoids, including PGE2. Cellular responses of PGE2 are exerted via four G-protein coupled receptors, including EP4 receptors. The COX-2/PGE2/EP4 axis plays crucial role in GBM development and progression, but it can be counteracted by COXIBs and 2,5-DMC. As presented in our study, COXIBs and 2,5-DMC downregulate the expression of both COX-2 and PGE2 EP4 (important to note - 2,5-DMC is not indicated in this part the Figure for clarity, as it is does not inhibit the enzymatic activity of COX-2). Moreover, the Wnt/β-catenin pathway is hyperactivated in GBM, mostly due to the epigenetic silencing of its extracellular antagonists. In the presence of Wnt ligand, the Frizzled receptors make a complex with low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) and Disheveled (Dvl), resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization. The degradation complex, consisting of Axin, GSK3β, CK1α and APC is not being formed. Subsequent translocation of β-catenin to the nucleus activates TCF/LEF-mediated transcription of β-catenin target genes including Axin2, c-MYC, CCND1, BIRC5, and NEDD9. COXIBs and 2,5-DMC downregulate their expression, attenuating the Wnt pathway