Aberrant expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin biosynthesis, can be found in the majority of cancers and is associated with an unfavorable outcome. Elevated levels of COX-2-derived prostaglandin E₂ (PGE₂) are associated with resistance to programmed cell death as well as stimulation of cell migration, cell proliferation, and angiogenesis. PGE₂ levels are regulated not only by its synthesis but also by its degradation. The key enzyme responsible for the biological inactivation of prostaglandins is NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). This enzyme catalyzes NAD⁺-linked oxidation of 15(S)-hydroxyl group of prostaglandins and lipoxins to yield inactive 15-keto metabolites. Genetic deletion of 15-pgdh in mice leads to increased tissue levels of PGE₂, which attribute to colon carcinogenesis. Recent studies have shown that expression of 15-PGDH is low in colon, lung, breast, bladder, and non-small cell lung cancer cells, which is associated with epigenetic silencing of the enzyme by DNA methylation and histone modification. While epidermal growth factor represses 15-PGDH expression, some chemopreventive agents induce 15-PGDH expression, which may partly account for the chemopreventive potential of these compounds. Therefore, 15-PGDH may consider as a novel molecular target for cancer chemoprevention and chemotherapy. (Cancer Prev Res 14, 201-207, 2009)

Keywords: 15-PGDH, PGE₂, COX-2, Tumor suppressor, Molecular target, Chemoprevention