Carcinogenesis, Vol. 21, No. 1, 15-21,
January 2000
© 2000 Oxford University Press
Cancer Biology |
Induction of cyclooxygenase expression and enhancement of malignant cell transformation by 2,3,7,8-tetrachlorodibenzo- p-dioxin
Department of Toxicology, University of Hamburg Medical School, and Department of Toxicology and Environmental Medicine of the Fraunhofer Society, D-20146 Hamburg and
1 Department of Obstetrics and Gynecology, Medical School University of Freiburg, D-79106 Freiburg, Germany
The potential role of arachidonic acid metabolism in the enhancement (promotion) of malignant transformation of C3H/M2 mouse fibroblasts by the tumor promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated using inhibitors of cyclooxygenase and lipoxygenase activities. The promoting effects of TCDD (1.5 pM) and of the reference tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA; 0.4 mM) on carcinogen (N-methyl-N'-nitro-N-nitrosoguanidine or 3-methylcholanthrene)-pre-treated fibroblasts was abolished by cotreatment with indomethacin, hydrocortisone, caffeic acid or nordihydroguaiaretic acid. A differential inhibition was found with N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide, a selective inhibitor of the cyclooxygenase isoenzyme COX-2: the promoting effect of TPA, but not that of TCDD, was abolished. Therefore, the role of the cyclooxygenase isoenzymes COX-1 and COX-2 during chronic exposure to TCDD was studied in more detail. Long-term treatment with TCDD (4–7 weeks) induced the expression of COX-1 and COX-2 mRNA in C3H/M2 fibroblasts (up to 2-fold). The enhanced expression of COX-2 protein in TCDD-treated fibroblasts was confirmed by western blot analysis. Concomitantly, the accumulation of the prostaglandins (PGs) PGE2 and 6-keto-PGF1
, which were identified as major metabolites of arachidonic acid in C3H/M2 cell cultures, was enhanced (~2-fold) following long-term treatment with TCDD (0.15 and 1.5 pM). The results suggest that the stimulation of arachidonic acid metabolism caused by a sustained cyclooxygenase induction is a critical event in the promoting action of TCDD in mouse fibroblasts in vitro. However, in contrast to TPA, the TCDD-mediated enhancement of malignant cell transformation may not specifically depend on the induction of COX-2 but, additionally, the induction of COX-1 activity may be necessary.
Abbreviations: COX-1/2, cyclooxygenase-1/2; EET, epoxyeicosatrienoic acid; GAPDH, glycerol aldehyde phosphate dehydrogenase; HETE, hydroxyeicosatetraenoic acid; MCA, 3-methylcholanthrene; MNNG, N-methyl-N'-nitro-N-nitrosoguanidine; NDGA, nordihydroguaiaretic acid; NS-398, N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TPA, 12-O-tetradecanoylphorbol-13-acetate.
2 To whom correspondence should be addressed at: Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV), FG 703, Thielallee 88-92, D-14195 Berlin, Germany Email: d.woelfle{at}bgvv.de
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