Dysregulation of ornithine decarboxylase activity, apoptosis and Bcl-2 oncoprotein in Syrian hamster embryo cells stage-exposed to di(2-ethylhexyl)phthalate and tetradecanoylphorbol acetate.
Perturbations of cell proliferation and death are considered as essential events in the process of carcinogenesis. Thus, two parameters, ornithine decarboxylase (ODC), an enzyme closely related to cell proliferation and transformation, and apoptotic phenomenon are profoundly modified. Using Syrian hamster embryo (SHE) cells, we have examined in the framework of two-stage carcinogenesis (initiation-promotion) the effects of a non-genotoxic [diethylhexylphthalate (DEHP)] or genotoxic [benzo[a]pyrene (BaP)] carcinogen or a non-carcinogenic compound [phthalic anhydride (AP)] on these parameters. Immunoreactive Bcl-2 and Bcl-xL proteins were also investigated following two-stage exposures. Whereas exposures to BaP, DEHP or AP alone did not provoke any modification of ODC activity, the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), strongly increased it. Using two-stage exposure protocol (xenobiotics first, then replacement by TPA-promoter), the ODC activity was higher than that obtained with TPA alone. This superinduction of ODC activity was observed only with the carcinogenic compounds DEHP and BaP. Following the same exposure protocol, spontaneous cellular apoptosis was decreased. Furthermore, Bcl-2 oncoprotein was also upregulated approximately 8- and 11-fold for BaP and DEHP respectively; meanwhile Bcl-xL protein rate did not change. The non-carcinogenic compound AP slightly inhibited spontaneous SHE cell death without ODC superinduction. Exogenous polyamines, putrescine, spermidine and spermine diluted in the medium did not inhibit spontaneous apoptosis. Although inhibition of apoptosis was not specific of carcinogenic compound, both superinduction of ODC activity and inhibition of apoptosis via Bcl-2 upregulation, may cooperate during early stages of the carcinogenic process.
Dhalluin
S
S
Laboratory of Cellular and Molecular Pharmacology, URA CNRS 1218, Faculty of Pharmacy, Châteney-Malabry, France.
Gate
L
L
Vasseur
P
P
Tapiero
H
H
Nguyen-Ba
G
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D006224:Cricetinae; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004622:Embryo, Mammalian / Q000187:drug effects; D008647:Mesocricetus; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D002273:Carcinogens; D019253:Proto-Oncogene Proteins c-bcl-2; D004051:Diethylhexyl Phthalate; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate