Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion

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 G₂ (PGG₂) and then prostaglandin H₂ (PGH₂) by cyclooxygenases (COXs). PGH₂ then becomes a substrate for a variety of PG synthases. These PG synthases are identified by the specific prostaglandin each one produces, namely, PGD₂ synthases (PGDSs), PGE₂ synthases (PGESs), (PGF_2α) synthase (PGFS), PGI₂ synthase (PGIS), or TxA₂ synthase (TXS). Both COX-2 and microsomal PGE synthase-1 (mPGES-1) are elevated in tumors. Export involves multidrug resistance-associated protein 4 (MRP4). In the extracellular milieu, PGs bind to G-protein-coupled receptors identified as DP1, DP2, EP1-4, FP, IP, and TP. Among these, EP receptors interact with G-stimulatory (Gs) or G-inhibitory (Gi) proteins stimulating downstream signals such as cAMP, Ca²⁺, inositol phosphates or IP3/Ca²⁺, and Rho. Catabolism involves uptake by PG transporter (PGT) and inactivation by NAD+ dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH).