Deciphering the role of the aryl hydrocarbon receptor (AhR) in lung cancer cells may help us to better understand the role of toxic AhR ligands in lung carcinogenesis, including cancer progression. We employed human lung carcinoma A549 cells to investigate their fate after continuous two-week exposure to model AhR agonists, genotoxic benzo[a]pyrene (BaP; 1 μM) and non-genotoxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 nM). While TCDD increased proliferative rate of A549 cells, exposure to BaP decreased cell proliferation and induced epithelial-to-mesenchymal transition (EMT)-like phenotype, which was associated with enhanced cell migration, invasion, and altered cell morphology. Although TCDD also suppressed expression of E-cadherin and activated some genes linked to EMT, it did not induce the EMT-like phenotype. The results of transcriptomic analysis, and the opposite effects of BaP and TCDD on cell proliferation, indicated that a delay in cell cycle progression, together with a slight increase of senescence (when coupled with AhR activation), favors the induction of EMT-like phenotype. The shift towards EMT-like phenotype observed after simultaneous treatment with TCDD and mitomycin C (an inhibitor of cell proliferation) confirmed the hypothesis. Since BaP decreased cell proliferative rate via induction of p21 expression, we generated the A549 cell model with reduced p21 expression and exposed it to BaP for two weeks. The p21 knockdown suppressed the BaP-mediated EMT-like phenotype in A549 cells, thus confirming that a delayed cell cycle progression, together with p21-dependent induction of senescence-related chemokine CCL2, may contribute to induction of EMT-like cell phenotype in lung cells exposed to genotoxic AhR ligands.

Department of Chemistry and Toxicology Veterinary Research Institute Brno Czech Republic

Department of Computer Science Czech Technical University Prague Czech Republic

Department of Cytokinetics Institute of Biophysics Academy of Sciences of the Czech Republic Brno Czech Republic

Department of Cytokinetics Institute of Biophysics Academy of Sciences of the Czech Republic Brno Czech Republic; Center of Biomolecular and Cellular Engineering International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

Department of Cytokinetics Institute of Biophysics Academy of Sciences of the Czech Republic Brno Czech Republic; Center of Biomolecular and Cellular Engineering International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic; Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Department of Genetic Toxicology and Nanotoxicology Institute of Experimental Medicine of the CAS Prague Czech Republic

Department of Pharmacology and Immunotherapy Veterinary Research Institute Brno Czech Republic

Linda Crnic Institute for Down Syndrome School of Medicine University of Colorado Anschutz Medical Campus Aurora Colorado 80045 USA; Department of Pharmacology School of Medicine University of Colorado Anschutz Medical Campus Aurora Colorado 80045 USA

References provided by Crossref.org

Lung cancer associated with combustion particles and fine particulate matter (PM2.5) - The roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR)