Abstract
An anti–tumor‐promoting effect of indomethacin and related nonsteroidal anti‐inflammatory drugs (NSAIDs) as well as the ability of the tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) to increase the level of prostaglandins in murine keratinocytes and mouse epidermis in vivo has been repeatedly documented. Here, the expression of prostaglandin H synthase (PGHS) isozymes, which are major targets of NSAIDs, was investigated in different stages of tumor development in mouse skin. Mouse epidermis in vivo constitutively expressed PGHS‐1. PGHS‐1 steady‐state levels remained unchanged upon induction of acute or chronic epidermal hyperplasia by TPA and in papillomas and carcinomas generated by the initiation‐promotion procedure, with 7,12‐dimethylbenz[a]anthracene as initiator and TPA as promoter. Thus, the elevated prostaglandin level in the acute hyperplastic epidermis was very likely due to PGHS‐2 induction. Repeated applications of TPA resulted in stationary hyperplasia and downregulation of PGHS‐2 expression and prostaglandin levels, suggesting that the epidermis had adapted to the TPA stimulus. In papillomas and carcinomas, however, constitutive overexpression of PGHS‐2 was found, with a large amount of prostaglandin E~2~ and prostaglandin F~2α~. Keratinocyte cell lines corresponding to different stages of tumor development also constitutively over‐expressed PGHS‐2. Considered with inhibitor studies, these data suggest that PGHS‐2 has a critical role in skin carcinogenesis. The anti–tumor‐promoting effect of the PGHS inhibitor indomethacin is specifically reversed by prostaglandin F~2α~, indicating that this prostaglandin type has a significant role in tumor development. © 1995 Wiley‐Liss Inc.