Figure 1

Eicosanoid metabolism and signaling. Cyclooxygenase (COX) enzymes convert arachidonic acid to the intermediate prostaglandin PGG₂, and thence to PGH₂. Subsequent enzymatic steps, catalyzed by specific isomerases, generate a variety of eicosanoid products. Thromboxane (TX) A₂ and prostacyclin (PGI₂), products of platelet COX-1 and endothelial COX-2, respectively, are thought to play opposing roles in cardiovascular biology. Most important in the context of epithelial tumorigenesis, PGE₂ is generated from PGH₂ through the action of PGE synthases. Signaling downstream of PGE₂ is initiated via interaction of PGE₂ with cognate PGE₂ receptors EP₁ to EP₄. PGE₂ signaling can be terminated via catabolism mediated by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Elevated PGE₂ levels in neoplastic tissues can thus be a consequence of COX-2 over-expression, PGE synthase modulation, and/or loss of 15-PGDH expression.