DIFFERENTIAL EXPRESSION OF PROSTAGLANDIN-H SYNTHASE ISOZYMES DURING MULTISTAGE CARCINOGENESIS IN MOUSE EPIDERMIS

被引:126
作者
MULLERDECKER, K [1 ]
SCHOLZ, K [1 ]
MARKS, F [1 ]
FURSTENBERGER, G [1 ]
机构
[1] GERMAN CANC RES CTR,DEPT BIOCHEM TISSUE SPECIF REGULAT,D-69120 HEIDELBERG,GERMANY
关键词
MULTISTAGE SKIN CARCINOGENESIS IN MOUSE; PROSTAGLANDIN H SYNTHASE ISOZYMES; NONSTEROIDAL ANTIINFLAMMATORY DRUG;
D O I
10.1002/mc.2940120106
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-2 alpha. Keratinocyte cell lines corresponding to different stages of tumor development also constitutively overexpressed 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-2 alpha, indicating that this prostaglandin type has a significant role in tumor development. (C) 1995 Wiley-Liss, Inc.
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页码:31 / 41
页数:11
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