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

K. Müller-Decker, A. Kopp-Schneider, F. Marks, K. Seibert, G. Fürstenberger

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)36-44
Number of pages9
JournalMolecular Carcinogenesis
Volume23
Issue number1
DOIs
StatePublished - Sep 1 1998

Keywords

  • Chemoprevention
  • Cyclooxygenase
  • Immunohistochemistry
  • Keratinocyte
  • Langerhans cell
  • Multistage skin carcinogenesis
  • Nonsteroidal anti-inflammatory drug
  • Prostaglandin H synthase
  • SC-58125

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