TY - JOUR
T1 - Localization of prostaglandin H synthase isoenzymes in murine epidermal tumors
T2 - Suppression of skin tumor promotion by inhibition of prostaglandin H synthase-2
AU - Müller-Decker, K.
AU - Kopp-Schneider, A.
AU - Marks, F.
AU - Seibert, K.
AU - Fürstenberger, G.
PY - 1998/9
Y1 - 1998/9
N2 - 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.
AB - 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.
KW - Chemoprevention
KW - Cyclooxygenase
KW - Immunohistochemistry
KW - Keratinocyte
KW - Langerhans cell
KW - Multistage skin carcinogenesis
KW - Nonsteroidal anti-inflammatory drug
KW - Prostaglandin H synthase
KW - SC-58125
UR - http://www.scopus.com/inward/record.url?scp=0031658940&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1098-2744(199809)23:1<36::AID-MC5>3.0.CO;2-F
DO - 10.1002/(SICI)1098-2744(199809)23:1<36::AID-MC5>3.0.CO;2-F
M3 - Article
C2 - 9766436
AN - SCOPUS:0031658940
SN - 0899-1987
VL - 23
SP - 36
EP - 44
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
IS - 1
ER -