3-Nitrofluoranthene (3-NF) but not 3-aminofluoranthene (3-AF) elicits apoptosis as well as programmed necrosis in Hepa1c1c7 cells |
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Authors: | Nana Asare Marit Låg Dominique Lagadic-Gossmann Mary Rissel Per Schwarze Jørn A Holme |
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Institution: | 1. Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway;2. Inserm U620, Group « Toxicity of Environmental Contaminants » labellisée Ligue contre le Cancer, 2 av Pr. Léon Bernard, 35043 Rennes cédex, France;3. UPRES EA SeRAIC, Université Rennes 1, IFR 140, 2 av Pr. Léon Bernard, 35043 Rennes cédex, France |
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Abstract: | In this study, we show that the environmental pollutant, 3-nitrofluoranthene (3-NF) but not its amine form, 3-aminofluoranthene (3-AF), induces apoptosis as well as regulated necrosis with necroptotic features in Hepa1c1c7 cells. Upon exposure to 3-NF, both typical apoptotic and necrotic cells were observed. A large number of the cells exhibited a characteristic partial nuclear chromatin condensation. Cycloheximide completely attenuated 3-NF-induced cell death. Activation of caspase-8, -9, and -3 were observed. Moreover, Z-VAD-FMK decreased the apoptotic cells, whereas the number of propidium iodide (PI)-positive cells with partial chromatin condensation was reduced by Nec-1, an inhibitor of receptor interacting protein (RIP-1). Cyp1a1, but not nitric oxide synthase (NOS), appears to be involved in activation of 3-NF to reactive metabolites. Increase in the number as well as size of lysosomes, myelinosomes, and activation of autophagy were also observed. 3-NF induced phosphorylation of ERK1/2, JNK and p38 MAPKs. Interestingly, while inhibitors of ERK1/2 and JNK reduced apoptotic as well as necrotic cell death, the p38 inhibitor, SB202190 reduced only the necrotic cell death. Taken together, 3-NF elicits both apoptosis and a caspase-independent programmed cell death (PCD) with autophagic characteristics. Conversely, with 3-AF, no apparent cytotoxic effects besides a reduction in cell proliferation was observed. |
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Keywords: | α-NF α-naphthoflavone AhR aryl hydrocarbon receptor 3-AF 3-aminofluoranthene B[a]P benzo[a]pyrene Cyp cytochrome P450 DMSO dimethyl sulphoxide ERK extracellular signal-regulated kinase FBS foetal bovine serum JNK c-jun N-terminal kinase L-NAME NG-nitro-l-arginine methyl ester MAPKs mitogen-activated protein kinases MAPKKs mitogen-activated protein kinase kinases Nec-1 necrostatin-1 3-NF 3-nitrofluoranthene nitro-PAHs nitro-polycyclic aromatic hydrocarbons 1-NP 1-nitropyrene NOS nitric oxide synthase PAHs polycyclic aromatic hydrocarbons PI propidium iodide PMSF phenylmethylsulphonyl fluoride RIP-1 receptor interacting protein-1 ROS reactive oxygen species RNS reactive nitrite species Z-VAD-FMK N-benzyloxycarbonyl-Val-Ala-Asp(O-Me)fluoromethyl ketone |
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