PCB153, TCDD and estradiol compromise the benzo[a]pyrene-induced p53-response via FoxO3a.

TCDD, polychlorinated biphenyls (PCB) and polycyclic aromatic hydrocarbons (PAH) coexist in the environment. However, there are few studies on combined effects of these compounds. We have studied the effect of TCDD, PCB153 and estradiol on p53 signaling induced by PAHs. We show that all three compounds amplified the accumulation of nuclear p53, elicited by benzo[a]pyrene (BaP) or dibenzo[al]pyrene (DBP). This effect was associated with an attenuated PAH-induced apoptosis and with decreased levels of phosphorylated FoxO3a Thr32. Thr32 phosphorylation of FoxO3a may promote a translocation of FoxO3a-p53 complex from nucleus to the cytoplasm, and the role of FoxO3a dephosphorylation was further studied. We found that inhibition of PP2A phosphatase restored levels of phosphorylated FoxO3a, led to cytosolic translocation of p53, and activated BaP-induced p53-mediated apoptosis. These results were confirmed by silencing FoxO3a with siRNA or by inhibiting 14-3-3 protein; also these treatments trapped BaP-induced p53 in the nucleus. Our data indicate interplay between p53, FoxO3a and 14-3-3 leading to an attenuated BaP induced apoptosis in cells co-exposed to TCDD, PCB 153 or estradiol.