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

Summary

Principal Investigator: JOHN JAMES LETTERIO
Abstract: 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.
Funding Period: 2013-04-01 - 2018-03-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. MODULATION OF INTESTINAL HOMEOSTASIS AND CANCER
    Leonard H Augenlicht; Fiscal Year: 2013
    ..abstract_text> ..
  2. The role of polyamine oxidase in antitumor drug response
    Robert A Casero; Fiscal Year: 2013
    ..abstract_text> ..
  3. The Sphingolipid Pathway in Colon Cancer Chemoprevention
    Toshihiko Kawamori; Fiscal Year: 2013
    ..abstract_text> ..
  4. Mechanisms for Benzo(a)pyrene-Induced Colon Cancer Exacerbation by Dietary Fat
    Aramandla Ramesh; Fiscal Year: 2013
    ..Our findings will serve as a prelude to conducting chemoprevention studies for CRC and help to synthesize drugs to prevent or delay the onset of colon cancer. ..
  5. Novel Sulindac Derivatives for Colon Cancer Chemoprevention
    Robert C Reynolds; Fiscal Year: 2013
    ..This multidisciplinary research proposal may lead to a novel strategy for colon cancer chemoprevention. ..
  6. Regulation of intestinal inflammation and tumorigenesis by Nlrp6
    Grace Y Chen; Fiscal Year: 2013
    ....
  7. S1P Lyase in colon cancer
    Julie D Saba; Fiscal Year: 2013
    ..In accomplishing these aims, we should achieve our two major goals: to elucidate the biology of SPL in colon cancer, and to develop chemopreventive strategies that work by reactivation of SPL. ..
  8. Mechanisms of tumor suppressor gene reactivation in colon cancer by berries
    Li Shu Wang; Fiscal Year: 2013
    ..We now propose to evaluate the anthocyanins in berries for their ability to demethylate and reactivate tumor suppressor genes in colon cancer. ..
  9. Understanding the role of Sgo1 in colorectal cancer
    Hiroshi Y Yamada; Fiscal Year: 2013
    ..Once validated, the model will aid identifying drugs that work for human population so far non- responsive to existing drugs. ..
  10. Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis
    CYNTHIA SEARS; Fiscal Year: 2013
    ..Colorectal cancer is a major public health problem being the second leading cause of cancer death in the United States in women and men. ..
  11. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013
    ..This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet. ..
  12. Regulation of Lipid Droplets and FOXO3 in Intestinal Epithelial Cell Proliferatio
    SUZANA SAVKOVIC; Fiscal Year: 2013
    ..Although mechanisms of colon cancer progression are complex, the inhibition of LDs may provide an effective blockade to tumor progression in patients with obesity promoted colonic tumor progression. ..