Non-dioxin-like PCBs interact with benzo[a]pyrene-induced p53-responses and inhibit apoptosis.
Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants often co-existing in contaminated environments. However, there are few studies on the effects of co-exposure, in particular on effects of pure NDL-PCB congeners and PAHs. We have evaluated the effects of some highly purified NDL-PCBs and benzo[a]pyrene (BP) on BP-induced Raf, Erk, Mdm2, p53 signaling and on BP-induced apoptosis and cell cycle arrest. PCBs (1 μM) were added to HepG2 cells 1h prior to BP and the incubation was stopped at 24 h. Employing Western blotting we found that NDL-PCBs (28, 101 and 153) amplified the BP-induced inactivating phosphorylation of Raf (pRaf Ser 259) and decreased levels of pErk Tyr 204. This treatment also resulted in the attenuation of BP-induced Mdm2 phosphorylation at Ser166 and amplification of the p53 Ser15 response. These effects were associated with an unexpected inhibition of BP-induced apoptosis. A dioxin-like PCB (DL-PCB 126) was used as reference and gave results that were predictable from previous studies, i.e. it attenuated BP-induced p53 response and apoptosis. In an effort to explain why the NDL-PCB-induced amplification of the p53 response was associated with a decreased apoptotic response we analyzed FoxO3a, which may translocate p53 to the cytoplasm. We found that NDL-PCBs reduced the level of phosphorylated FoxO3a at Thr32. This phosphorylation promotes a cytoplasmic translocation of FoxO3a and p53 and our data suggest that NDL-PCBs may inhibit BP-induced apoptosis by preventing a FoxO3a-dependent translocation of p53 to the cytoplasm.
Al-Anati
Lauy
L
Institute of Environmental Medicine, Karolinska Institutet, S-17177, Stockholm, Sweden. Lauy.al-anati@ki.se
Högberg
Johan
J
Stenius
Ulla
U
D017209:Apoptosis / Q000187:drug effects*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048490:raf Kinases / Q000378:metabolism
D004785:Environmental Pollutants; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D011078:Polychlorinated Biphenyls; D051736:Proto-Oncogene Proteins c-mdm2; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases