Al-Anati Lauy, Kadekar Sandeep, Högberg Johan, Stenius Ulla
Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Chem Biol Interact. 2014 Aug 5;219:159-67. doi: 10.1016/j.cbi.2014.06.007. Epub 2014 Jun 19.
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.
2,3,7,8-四氯二苯并对二恶英（TCDD）、多氯联苯（PCB）和多环芳烃（PAH）在环境中共同存在。然而，关于这些化合物联合效应的研究很少。我们研究了TCDD、PCB153和雌二醇对PAHs诱导的p53信号传导的影响。我们发现，这三种化合物均增强了由苯并[a]芘（BaP）或二苯并[a,l]芘（DBP）引起的细胞核p53的积累。这种效应与PAH诱导的细胞凋亡减弱以及磷酸化的叉头框蛋白O3a（FoxO3a）苏氨酸32位点（Thr32）水平降低有关。FoxO3a的Thr32磷酸化可能促进FoxO3a-p53复合物从细胞核向细胞质的转运，并且对FoxO3a去磷酸化的作用进行了进一步研究。我们发现，抑制蛋白磷酸酶2A（PP2A）可恢复磷酸化FoxO3a的水平，导致p53向细胞质转运，并激活BaP诱导的p53介导的细胞凋亡。用小干扰RNA（siRNA）沉默FoxO3a或抑制14-3-3蛋白证实了这些结果；此外，这些处理使BaP诱导的p53滞留在细胞核中。我们的数据表明p53、FoxO3a和14-3-3之间存在相互作用，导致在同时暴露于TCDD、PCB 153或雌二醇的细胞中BaP诱导的细胞凋亡减弱。
