Expression of cyclooxygenase 2 in human malignant melanoma.
Cyclooxygenase (COX)-2 is an inducible enzyme involved in production of prostaglandins in inflammatory processes. There is now increasing evidence that a constitutive expression of COX-2 plays a role in development and progression of malignant epithelial tumors. In the present study we investigated expression and function of COX-2 in malignant melanoma. Expression of COX-2 was determined by immunohistochemistry in 28 cases of primary skin melanoma and 4 benign nevi. We show that COX-2 was expressed in 26 cases (93%) of melanomas, with a moderate to strong expression in 19 cases (68%). Benign nevi as well as normal epithelium were negative in all cases. A constitutive expression of COX-2 mRNA and protein was found in five melanoma cell lines (A375, MeWo, SK-Mel-13, SK-Mel-28, and IGR-37) by using Northern blot as well as immunoblotting. All melanoma cell lines produced prostaglandin (PG) E2 between 468 and 3500 pg/ml as determined by ELISA. Treatment with NS-398 (50 microM), a specific inhibitor of COX-2, suppressed PGE2 production of all melanoma cell lines by 50-96%. The IC50 for inhibition of PGE2 production by NS-398 was determined as 4 microM, indicating that NS-398 acts via inhibition of the COX-2 isoenzyme. We could show that proliferation of melanoma cell lines was not influenced by treatment with NS-398 in concentrations up to 100 microM. However, NS-398 reduced Matrigel invasion of all five malignant melanoma cell lines by 50-68%. Our results indicate that COX-2 is expressed in malignant melanomas and may be involved in regulation of melanoma invasion. It remains to be investigated whether selective inhibitors of COX-2 might be useful for prevention or treatment of malignant melanoma.
Denkert
C
C
Institute of Pathology, Charité Hospital, Berlin, Germany.
Köbel
M
M
Berger
S
S
Siegert
A
A
Leclere
A
A
Trefzer
U
U
Hauptmann
S
S
D001672:Biocompatible Materials; D002455:Cell Division / Q000187:drug effects; D003094:Collagen; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004338:Drug Combinations; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D007797:Laminin; D008545:Melanoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D011509:Proteoglycans; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D001672:Biocompatible Materials; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D007527:Isoenzymes; D007797:Laminin; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011509:Proteoglycans; D012333:RNA, Messenger; D013449:Sulfonamides; C059485:matrigel; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D003094:Collagen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone