Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) are upregulated in inflammation and cancer. This results in the production of prostaglandin E2 (PGE2), which binds to and activates G-protein-coupled prostaglandin receptors ( ). Selectively targeting the COX-2/mPGES-1/PGE2/ axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM). Interactions with the ECM are mediated by cell surface integrins by “outside-in signaling” through Src and focal adhesion kinase (FAK) and/or “inside-out signaling” through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE2/ axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy. 1. The Prostaglandin Pathway Prostaglandins (PGs) and other eicosanoids are bioactive lipids that impact normal development, tissue homeostasis, inflammation, and cancer progression [1]. Prostaglandins are derived from the 20-carbon chain fatty acid, arachidonic acid (AA) stored in the plasma membrane of cells [2, 3]. As a storage mechanism, dietary AA is coupled to CoA molecules by acyl-coenzyme A (acyl-CoA) synthetases [4]. In turn, fatty acyltransferases utilize arachidonyl-CoA donor molecules to insert AA into membrane phospholipids [2, 3]. Membrane phospholipids generally retain AA until an appropriate stimulus catalyzes its release by phospholipase A2 [5–8] (Figure 1). Figure 1: Eicosanoid metabolism. Arachidonic acid (AA) is an essential dietary fatty acid that is transported into cells and stored in membrane phospholipids. First AA is coupled to acyl-CoA by acyl-coenzyme A synthetases (ACLS). Fatty acyltransferases (FACT) then insert AA into membrane phospholipids. Cytoplasmic phospholipase A2 (cPLA2) releases AA from membrane phospholipids after agonist stimulation. In turn, free AA is converted to prostaglandin G 2 (PGG 2) and then prostaglandin H 2 (PGH 2) by cyclooxygenases (COXs). PGH 2 then becomes a substrate for a variety of PG synthases. These PG synthases are identified by the specific prostaglandin each one produces, namely, PGD 2 synthases (PGDSs), PGE 2 synthases (PGESs), (PGF 2α) synthase (PGFS), PGI 2
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