Role of cell signalling involved in induction of apoptosis by benzo[a]pyrene and cyclopenta[c,d]pyrene in Hepa1c1c7 cells.

The reactive metabolites of benzo[a]pyrene (B[a]P) and cyclopenta[c,d]pyrene (CPP) induced an accumulation/phosphorylation of p53 in Hepa1c1c7 cells, whereas inhibition of p53 reduced the apoptosis. Judged by the inhibiting effect of wortmannin, phosphatidyl-inositol-3 (PI-3) kinases such as DNA-dependent protein kinase (DNA-PK), ATM (ataxia-telangiectasia mutated), and/or ATR (ATM related kinase), appeared to be involved in the DNA damage recognition and the B[a]P-/CPP-induced accumulation of p53. B[a]P and CPP also induced phosphorylation of jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK). While inhibition of JNK had no effects on the B[a]P-/CPP-induced apoptosis, inhibition of p38 MAPK activity reduced this effect. Interestingly, survival signals such as phosphorylation of Akt and Bad seemed to be induced by the B[a]P-/CPP-compounds. Furthermore, also extracellular signal-regulated kinase (ERK)1/2 was activated and seemed to function as a survival signal in B[a]P-/CPP-induced apoptosis. Copyright 2004 Wiley-Liss, Inc.