Exposure to
polycyclic aromatic hydrocarbons (PAHs) has been positively associated with
prostate cancer, but knowledge of the formation of PAH-
DNA adducts and related genotoxic events in prostatic cells is limited. In the present study,
benzo[a]pyrene (BaP), a potent mutagenic PAH, formed significant levels of
DNA adducts in cell lines derived from human prostate
carcinoma. When analyzing the effect of BaP on the induction of
CYP1 enzymes participating in the metabolic activation of PAHs in LNCaP cells, we found that BaP induced expression of
CYP1A1 and
CYP1A2, but not CYP1B1
enzyme. Despite a significant amount of
DNA adducts being formed by BaP and, to a lesser extent also by another strong
genotoxin,
dibenzo[a,l]pyrene, neither apoptosis nor cell-cycle arrest were induced in LNCaP cells. LNCaP cells were not sensitized to the induction of apoptosis by PAHs even through inhibition of the
phosphoinositide-3-kinase/Akt pro-survival pathway. The lack of apoptosis was not due a disruption of expression of pro-apoptotic and pro-survival members of the Bcl-2 family of apoptosis regulators. In contrast to other genotoxic stimuli, genotoxic PAHs failed to induce
DNA double-strand breaks, as illustrated by the lack of phosphorylation of
histone H2AX or checkpoint kinase-2. BaP did not activate p53, as evidenced by the lack of p53 accumulation, phosphorylation at Ser15, or induction of p53 transcriptional targets. Taken together, although genotoxic PAHs produced significant levels of
DNA adducts in a model of human prostate
carcinoma cells, they did not activate the mechanisms leading to elimination of cells with significant damage to
DNA, presumably due to their failure to activate the p53-dependent DNA damage response.