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

Abstract

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.

Benzo[a]pyrene-induced cell cycle progression occurs via ERK-induced Chk1 pathway activation in human lung cancer cells

“…Activation of MAPK signaling leads to diverse cellular responses, including cell proliferation, differentiation, and apoptosis [7,8]. Other findings have revealed that B[a]P rapidly activates p38 MAPK and c-Jun N-terminal kinase (JNK) in lung cells [9][10][11]. Research in mouse hepatoma cell lines found that B[a]P induces apoptosis by causing p53 accumulation and phosphorylation and downregulating the Bcl-2 proteins Bcl-xl, Bad, and Bid [9].…”

“…Other findings have revealed that B[a]P rapidly activates p38 MAPK and c-Jun N-terminal kinase (JNK) in lung cells [9][10][11]. Research in mouse hepatoma cell lines found that B[a]P induces apoptosis by causing p53 accumulation and phosphorylation and downregulating the Bcl-2 proteins Bcl-xl, Bad, and Bid [9]. Furthermore, reactive metabolites of B[a]P induce Bax translocation to the mitochondria as well as p53 accumulation and translocation to the nucleus.…”

c-Jun NH2-Terminal Kinase–Related Na+/H+ Exchanger Isoform 1 Activation Controls Hexokinase II Expression in Benzo(a)Pyrene-Induced Apoptosis

“…Many of these compounds exhibit carcinogenic effects due to their metabolism by cytochromes P450, thereby forming highly reactive metabolites that bind to DNA (1). This genotoxicity is also the major trigger of apoptotic induction in several cellular models (2).…”

Cellular Defense Mechanisms against Benzo[a]pyrene in Testicular Leydig Cells: Implications of p53, Aryl-Hydrocarbon Receptor, and Cytochrome P450 1A1 Status

“…Caspase-3 activation can be suppressed by up-regulation of X chromosome-linked inhibitor of apoptosis protein (XIAP) in many cell types (18). Although the cell signaling mechanism(s) by which B[a]P induces apoptosis has been well demonstrated particularly in Hepa1c1c7 cells (13,19), the precise biochemical and cellular mechanisms involved in cytoprotection and antiapoptosis after B[a]P exposure are relatively unknown. We hypothesized herein that the cytoprotective and antiapoptotic characteristics of Leydig cells against B[a]P might be primarily due to the insufficiency of CYP1A1 expression and activity.…”