Abstract
Abstract Polycyclic aromatic hydrocarbons and heavy metals are widely distributed in the environment. Among these, benzo(a)pyrene and cadmium are two of the known human carcinogens. Despite their ubiquitous occurrence little is known about their specific effects on intracellular signaling events. Here, we investigate the effects of benzo[a]pyrene-7,8-dione (BaPD), a genotoxic metabolite of benzo(a)pyrene, and cadmium on human bronchial/tracheal epithelial cells (hBEC). The mitogen-activated protein kinases (MAPKs), a family of serine/threonine kinases, transduce signals that lead to diverse cellular responses such as cell growth, differentiation, proliferation, apoptosis, and stress responses to environmental stimuli. Apoptosis is an important protective response to DNA damage. Caspase-3 and caspase-7 are major executioners of apoptosis, with caspase-3 being reported as the primary regulator of apoptotic DNA fragmentation. The p53 tumor suppressor gene is the most important inducer of apoptosis and plays an important role in DNA repair and cell cycle arrest. The modulation of p53 tumor suppressor function is a universal step in the development of human cancer. Akt/protein kinase B is frequently hyperactivated to ensure cell survival. Here, we propose that the exposure of hBEC to benzo(a)pyrene-7,8-dione (BaPD) and cadmium chloride (CdCl2) induce caspase mediated apoptosis, disrupt MAP kinase signaling and p53 functions, and cause cell cycle arrest. Methods: hBEC were exposed to a range of BaPD and CdCl2 concentrations (1.25-100 μg/ml) for 6 and 24h. Levels of caspase 3/7 were quantified using caspase 3/7 glo assay. Phosphorylation of P38-MAPK (Thr180/Y182), Erk1/2 (Thr202/Tyr204), p53 (Ser15), Akt (Ser473) and MDM2 (Ser166) were performed by western blotting. Statistical tests were conducted using GraphPad Prism software at a significance level of 0.05. Results: We observed that both CdCl2 and BaPD initiated caspase 3/7 activity at 1h, but maximum activity was noticed at 4h for CdCl2 and 6h for BaPD followed by reductions at 24h. A dose dependent phosphorylation of p38MAPK was noticed for both CdCl2 and BaPD at 6h, followed by a decrease at 24h. While Erk1/2 and Akt were activated during the first 6h after treatment with CdCl2, this effect was not observed in cells treated with BaPD. Both BaPD and CdCl2 induced p53 accumulation and cell cycle arrest at sub-G0/G1 phase. An apparent inverse correlation was observed between MDM2 phosphorylation and total p53 levels. Conclusion: Our results suggest that CdCl2 and BaPD modulate Akt, MAPKs, p53-MDM2 activity and cause cell cycle arrest in hBEC. Citation Format: Jibanananda Mishra, Berrin Serdar. Effects of benzo(a)pyrene-7,8-dione and cadmium on Akt/protein kinase B, MAPK and p53-MDM2 activity in primary human bronchial/tracheal epithelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3181. doi:10.1158/1538-7445.AM2014-3181
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