Induction of cyclooxygenase expression and enhancement of malignant cell transformation by 2,3,7,8-tetrachlorodibenzo-p-dioxin

被引:45
作者
Wölfle, D
Marotzki, S
Dartsch, D
Schäfer, W
Marquardt, H
机构
[1] Univ Hamburg, Sch Med, Dept Toxicol, D-20146 Hamburg, Germany
[2] Fraunhofer Soc, Dept Toxicol & Environm Med, D-20146 Hamburg, Germany
[3] Univ Freiburg, Sch Med, Dept Obstet & Gynecol, D-79106 Freiburg, Germany
关键词
D O I
10.1093/carcin/21.1.15
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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) PGE(2) and 6-keto-PGF(1 alpha), which were identified as major metabolites of arachidonic acid in C3H/M2 cell cultures, was enhanced (similar to 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.
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页码:15 / 21
页数:7
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