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Role of 15-Hydroxyprostaglandin Dehydrogenase as a Tumor Suppressor and Its Underlying Molecular Mechanism
Cancer Prevention Research 2009³â 14±Ç 3È£ p.201 ~ p.207
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Abstract
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.
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15-PGDH, PGE2, COX-2, Tumor suppressor, Molecular target Chemoprevention
KMID :
1140120090140030201
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15-PGDH may consider as a novel molecular target for cancer chemoprevention and chemotherapy.