Localization of prostaglandin H synthase isoenzymes in murine epidermal tumors: suppression of skin tumor promotion by inhibition of prostaglandin H synthase-2

Mol Carcinog. 1998 Sep;23(1):36-44. doi: 10.1002/(sici)1098-2744(199809)23:1<36::aid-mc5>3.0.co;2-f.


The growth factor- and phorbol ester-inducible prostaglandin H synthase (PGHS)-2 has been found to be constitutively overexpressed in epidermal tumors generated by the initiation-promotion protocol in murine skin, whereas the expression of PGHS-1 does not change under these conditions. In this paper we report the intra-tumor distribution of the aberrantly expressed PGHS-2 and the cancer chemopreventive activity of a specific PGHS-2 inhibitor. By immunohistochemical methods using isoenzyme-specific antibodies, we found that the PGHS-1 protein was expressed in keratinocytes and Langerhans cells dispersed throughout the epithelial part of papillomas and squamous cell carcinomas and in inflammatory infiltrates occasionally seen in these tumors. A uniform pattern of PGHS-2 expression was observed in the basal keratinocytes of papillomas and in the follicular keratinocytes of carcinomas. In addition, Langerhans cells as well as tumor-associated inflammatory infiltrates exhibited PGHS-2-specific immunoreactivity. PGHS-2-catalyzed prostaglandin synthesis stimulated by the phorbol ester 12-O-tetradecanoylphorbol-13 acetate (TPA) in mouse epidermis in vivo was dose-dependently suppressed by topical administration of SC-58125, a specific PGHS-2 inhibitor. TPA-induced edema formation, epidermal DNA synthesis, and mitotic activity were not impaired by SC-58125 applied at a dose that inhibited TPA-induced prostaglandin E2 synthesis. However, the repetitive epicutaneous administration of SC-58125 substantially and significantly suppressed papilloma development. Malignant progression of papillomas was slightly retarded by the drug. These results indicate that aberrant expression of PGHS-2 in epidermal tumors may be a relevant target for prevention of epidermal cancer development in experimental animals and that the PGHS-2-specific inhibitor SC-58125, which is a potent inhibitor of tumor promotion in mouse skin, may be important for cancer chemoprevention in humans as well.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase Inhibitors / pharmacology*
  • Dinoprostone / metabolism
  • Epidermis / drug effects
  • Epidermis / metabolism
  • Female
  • Immunohistochemistry
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism*
  • Mice
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Pyrazoles / pharmacology*
  • Skin Neoplasms / enzymology*
  • Tetradecanoylphorbol Acetate / pharmacology


  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Pyrazoles
  • 1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone
  • Tetradecanoylphorbol Acetate