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

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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. Mol. Carcinog. 23:36–44, 1998.