Activation of ERK1/2 and p38 kinases by polycyclic aromatic hydrocarbons in rat liver epithelial cells is associated with induction of apoptosis.
Deregulation of various signaling pathways, linked either to induction of cell proliferation or to modulation of cellular differentiation and apoptosis, has been proposed to contribute to carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). In the present study, we investigated effects of the PAHs previously shown to induce cell proliferation and/or apoptosis in contact-inhibited rat liver epithelial WB-F344 cells, with an aim to define the role of mitogen-activated protein kinases in both events. We found that only strong genotoxin dibenzo[a,l]pyrene (DBalP) activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 kinase, but not c-Jun N-terminal kinases (JNKs), at concentrations inducing both apoptosis and phosphorylation of p53 tumor suppressor at serine 15 residue. In contrast, the PAHs stimulating cell proliferation in WB-F344 cell line had no effect on activation of ERK1/2, p38 or JNKs. Synthetic inhibitors of ERK1/2 activation (U0126) or p38 kinase activity (SB203580) prevented both apoptosis and induction of p53 phosphorylation by DBalP. Pifithrin-alpha, inhibitor of p53 transcriptional activity, prevented induction of apoptosis and activation of ERK1/2 and p38. Taken together, our data suggest that both ERK1/2 and p38 are activated in response to DBalP and that they might be involved in regulation of cellular response to DNA damage induced by DBalP, while neither kinase is involved in the release from contact inhibition induced by PAHs.
Andrysík
Zdenek
Z
Laboratory of Cytokinetics, Institute of Biophysics, ASCR, 612 65 Brno, Czech Republic.
Machala
Miroslav
M
Chramostová
Katerina
K
Hofmanová
Jirina
J
Kozubík
Alois
A
Vondrácek
Jan
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D011084:Polycyclic Aromatic Hydrocarbons; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases