Small Molecule Induction of 15-PGDH: A Target in Colon Cancer Chemoprevention

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DESCRIPTION (provided by applicant): The cyclooxygenase pathway is considered an important target in the chemoprevention and therapy of cancer. The prostaglandin (PG) degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), functions as an endogenous inhibitor of the colonic COX-2 pathway and as a colon tumor suppressor gene. There is now accumulating evidence that support the hypothesis that expression of 15-PGDH plays an important role in mucosal epithelial homeostasis, and that repression of 15-PDGH expression by inflammatory mediators may be an important step in colitis associated colon carcinogenesis. In particular, recent data indicate that the loss of 15-PGDH expression is an important determinant of the response to inhibitors of COX-2 in the context of cancer chemoprevention. Therefore, agents with a capacity to induce the expression of 15-PGDH may serve as an effective form of cancer chemoprevention, and may either enhance the response to or overcome the resistance to COX-2 inhibitors (such as celecoxib or Celebrex(R)). 15-PGDH is highly expressed in normal colon mucosa, but the expression of this enzyme is invariably lost in human colon cancers. In mice, a disruption of the gene encoding 15-PGDH leads to an increase in susceptibility to colon cancer, enhancing the susceptibility of the normally resistant C57BL/6J strain to colon tumor induction with azoxymethane (AOM) and leading to an increase in colon tumors arising in the APC+/Min (multiple intestinal neoplasia) mouse model.3 Mechanisms leading to this loss of 15-PGDH expression are not entirely clear, but a role for increased expression of histone deacetylase (HDAC) in human colon cancers in the repression of 15-PDGH expression has been demonstrated through a mechanism that involves the transcriptional repressor, Snail.5 In addition, repression of 15-PGDH by epidermal growth factor signaling and by inflammatory cytokines (TNF-a) has also been demonstrated. These data support the hypothesis that inflammation may promote tumorigenesis, in part, through coordinated effects on activities of enzymes of both prostaglandin biosynthesis and metabolism. To address this question, our laboratory now explores the ability of triterpenoids (natural and synthetic) to induce the expression of 15-PGDH, and whether an induction of this enzyme is associated with effective chemoprevention of colon cancer. The triterpenoids are a class of multifunctional small molecules that regulate multiple signaling pathways and have demonstrated chemopreventive activity in specific preclinical models of cancer. Our preliminary data demonstrate the ability of triterpenoids to: a) induce 15-PGDH in a TGF-b-dependent manner, b) restore expression of 15-PGDH in a model of colitis associated colon cancer and c) prevent clinical symptoms of IBD in this model. The observations outlined above are the basis for our hypothesis that colon cancer chemoprevention by triterpenoids requires a TGF-b-dependent induction of 15- PGDH.