Enhancement of carcinogen-induced malignant cell transformation by prostaglandin F(2 alpha).
The enhancement of carcinogen-induced malignant transformation of C3H/M2 mouse fibroblasts by the tumor promoters 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with the induction of cyclooxygenase expression and the stimulation of prostaglandin (PG) formation. Therefore, the potential of PGs, i.e., PGF(2alpha) and PGE(2), for tumor promotion was studied in the two-step C3H/M2 cell transformation assay, a model of the multi-step process of carcinogenesis. The transformation of fibroblasts was clearly enhanced by the addition of PGF(2alpha) in the promotion phase after pretreatment with a subthreshold dose of a carcinogen (3-methylcholanthrene or N-methyl-N'-nitro-N-nitrosoguanidine). No enhancement of cell transformation was observed in cells without carcinogen-pretreatment, i.e., PGF(2alpha) had no tumor initiating potential. The promotional effect was dose-dependent with a maximum at 16 nM PGF(2alpha). PGE(2) had no significant effect in this assay. Furthermore, PGF(2alpha) (but not PGE(2)) clearly reduced the inhibition of TPA-induced promotion by NS-398, an isozyme-specific inhibitor of cyclooxygenase-2. The inhibition of TPA- or TCDD-induced promotion by the non-specific cyclooxygenase inhibitor indomethacin was not affected by co-treatment with PGF(2alpha) and PGE(2). Our data suggest that PGF(2alpha) acts as an endogenous promoter of cell transformation implying that it may also be critically involved in tumor promoter-induced signalling transfer cascades ultimately triggering the process of carcinogenesis.
Wölfle
Detlef
D
Federal Institute for Risk Assessment (BfR), FG123, Thielallee 88-92, D-14195 Berlin, Germany. d.woelfle@bfr.bund.de
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000633:toxicity*; D015232:Dinoprostone / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects; D008748:Methylcholanthrene / Q000633:toxicity; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D051379:Mice; D008809:Mice, Inbred C3H; D009578:Nitrobenzenes / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000633:toxicity
D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D000072317:Polychlorinated Dibenzodioxins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D008769:Methylnitronitrosoguanidine; D008748:Methylcholanthrene; D015237:Dinoprost; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate