title: Signalling pathways involved in 1-nitropyrene (1-NP)-induced and 3-nitrofluoranthene (3-NF)-induced cell death in Hepa1c1c7 cells.
abstract: We previously reported that 1-nitropyrene (1-NP) and 3-nitrofluoranthene (3-NF) elicited apoptotic cell death as well as non-apoptotic programmed cell deaths (PCDs) with paraptotic and necroptotic characteristics, respectively. In the present study, we have further confirmed and extended these findings. Flow cytometric analyses of 1-NP-exposed/3NF-exposed Hepa1c1c7 cells revealed that caspase-3 was only activated in the subpopulation of cells corresponding to that with classic apoptotic morphology. Immunocytochemical analysis indicated that leucocyte elastase inhibitor-derived DNaseII (LEI/L-DNaseII), apoptosis-inducing factor (AIF) and endonuclease G (EndoG) were more clearly translocated to the nucleus following 3-NF exposure than after 1-NP. These 3-NF-induced changes in AIF and EndoG translocation were reduced by necrostatin-1, an inhibitor of necroptotic cell death. Both compounds lead to accumulation of lipid droplets and induced DNA damage. Activation of checkpoint kinase (CHK) 1 and H2AX, but not ataxia telangiectasia mutated and CHK2, were observed. Furthermore, inhibition of p53 using pifithrin-alpha reduced the cell death induced by both compounds, suggesting a role of DNA damage/CHK1/p53 pathway in the death process. 1-NP-induced cell death was in addition characterized by increased oxidative damage and intracellular accumulation of Ca(2+). These findings further support the notion that 1-NP elicited apoptotic cell death and PCD with paraptotic characteristics, while 3-NF induced apoptosis and a PCD with necroptotic features.
authors.affiliation: Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404 Nydalen, N-0403 Oslo, Norway.
authors.forename: Nana
authors.initials: N
authors.lastname: Asare
authors.forename: Xavier
authors.initials: X
authors.lastname: Tekpli
authors.forename: Mary
authors.initials: M
authors.lastname: Rissel
authors.forename: Anita
authors.initials: A
authors.lastname: Solhaug
authors.forename: Nina
authors.initials: N
authors.lastname: Landvik
authors.forename: Valerie
authors.initials: V
authors.lastname: Lecureur
authors.forename: Normand
authors.initials: N
authors.lastname: Podechard
authors.forename: Gunnar
authors.initials: G
authors.lastname: Brunborg
authors.forename: Marit
authors.initials: M
authors.lastname: Låg
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagadic-Gossmann
authors.forename: Jørn A
authors.initials: JA
authors.lastname: Holme
mesh_terms: D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000096:biosynthesis; D064007:Ataxia Telangiectasia Mutated Proteins; D052160:Benzothiazoles / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D016923:Cell Death; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004706:Endodeoxyribonucleases / Q000096:biosynthesis; D005449:Fluorenes / Q000633:toxicity*; D006657:Histones / Q000096:biosynthesis; D006801:Humans; D011494:Protein Kinases / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011721:Pyrenes / Q000633:toxicity*; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
chemical_list: D051033:Apoptosis Inducing Factor; D052160:Benzothiazoles; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005449:Fluorenes; D006657:Histones; D011721:Pyrenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014050:Toluene; C121565:pifithrin; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D004706:Endodeoxyribonucleases; C052391:endonuclease G; C019329:deoxyribonuclease II; C033643:3-nitrofluoranthene; C032668:1-nitropyrene