15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers

Marked increased expression of cyclooxygenase 2 (COX-2), a prostaglandin-synthesizing Enzyme that is pharmacologically inhibited by nonsteroid anti-inflammatory-type drugs, is a major early oncogenic event in the genesis of human colon neoplasia. We report that, in addition to inducing expression of COX-2, colon cancers further target the prostaglandin biogenesis pathway by ubiquitously abrogating expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading Enzyme that physiologically antagonizes COX-2. We find that 15-PGDH transcript and protein are both highly expressed by normal colonic epithelia but are nearly undetectable in colon cancers. Using gene transfection to restore 15-PGDH expression in colon Cancer cells strongly inhibits the ability of these cells to form tumors in immune-deficient mice and demonstrates 15-PGDH to have functional colon Cancer tumor suppressor activity. In interrogating the mechanism for 15-PGDH expression loss in colon Cancer, we determined that colonic 15-PGDH expression is directly controlled and strongly induced by activation of the TGF-beta tumor suppressor pathway. These findings thus delineate an enzymatic pathway that induces colon Cancer suppression, a pathway that is activated by TGF-beta and mediated by 15-PGDH.