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Aryl hydrocarbon receptor mediates benzo[a]pyrene-induced metabolic reprogramming in human lung epithelial BEAS-2B cells. 2021

Guozhu Ye, and Han Gao, and Xu Zhang, and Xinyu Liu, and Jinsheng Chen, and Xu Liao, and Han Zhang, and Qiansheng Huang
Center for Excellence in Regional Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, 1799 Jimei Road, Xiamen 361021, China; Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, 1799 Jimei Road, Xiamen 361021, China. Electronic address: gzye@iue.ac.cn.

Polycyclic aromatic hydrocarbon exposure accelerates the initiation and progression of lung cancer through aryl hydrocarbon receptor (AHR) signaling. Metabolic reprogramming is a hallmark of cancer. However, how AHR reprograms metabolism related to the malignant transformation in of benzo[a]pyrene (BaP)-exposed lung cells remains unclear. After confirming that BaP exposure activated AHR signaling and relevant downstream factors and then promoted epithelial-mesenchymal transition, an untargeted metabolomics approach was employed to discover AHR-mediated metabolic reprogramming and potential therapeutic targets in BaP-exposed BEAS-2B cells. We found that 52 metabolites were significantly altered in BaP-exposed BEAS-2B cells and responsive to resveratrol (RSV) intervention. Pathway analysis revealed that 28 and 30 metabolic pathways were significantly altered in response to BaP exposure and RSV intervention, respectively. Notably, levels of most amino acids were significantly decreased, while those of most fatty acids were significantly increased in BaP-exposed BEAS-2B cells, and above changes were abolished by RSV intervention. Besides, levels of amino acids and fatty acids were highly correlated with those of many metabolites and AHR signaling upon BaP exposure and RSV intervention (the absolute values of Pearson correlation coefficients above 0.8). We further discovered a decrease in peroxisome proliferator-activated receptor (PPAR) A/G signaling and an increase in fatty acid import by the transporter FATP1 in BaP-exposed BEAS-2B cells. Furthermore, inhibition of AHR signaling by CH-223191 abolished BaP-induced repression of PPARA/G signaling and activation of FATP1 in BEAS-2B cells, demonstrating the regulatory role of AHR signaling in fatty acid accumulation via mediating PPARA/G-FATP1 signaling. These data suggested amino acid and fatty acid metabolism, AHR and PPAR-FATP1 signaling as potential therapeutic targets for intervening BaP-induced toxicity and related diseases. As far as we known, fatty acid accumulation and high correlations of AHR signaling with amino acid and fatty acid metabolism are novel phenomena discovered in BaP-exposed lung epithelial cells.

UI MeSH Term Description Entries
D008168 Lung Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood. Lungs
D004847 Epithelial Cells Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells. Adenomatous Epithelial Cells,Columnar Glandular Epithelial Cells,Cuboidal Glandular Epithelial Cells,Glandular Epithelial Cells,Squamous Cells,Squamous Epithelial Cells,Transitional Epithelial Cells,Adenomatous Epithelial Cell,Cell, Adenomatous Epithelial,Cell, Epithelial,Cell, Glandular Epithelial,Cell, Squamous,Cell, Squamous Epithelial,Cell, Transitional Epithelial,Cells, Adenomatous Epithelial,Cells, Epithelial,Cells, Glandular Epithelial,Cells, Squamous,Cells, Squamous Epithelial,Cells, Transitional Epithelial,Epithelial Cell,Epithelial Cell, Adenomatous,Epithelial Cell, Glandular,Epithelial Cell, Squamous,Epithelial Cell, Transitional,Epithelial Cells, Adenomatous,Epithelial Cells, Glandular,Epithelial Cells, Squamous,Epithelial Cells, Transitional,Glandular Epithelial Cell,Squamous Cell,Squamous Epithelial Cell,Transitional Epithelial Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001564 Benzo(a)pyrene A potent mutagen and carcinogen. It is a public health concern because of its possible effects on industrial workers, as an environmental pollutant, an as a component of tobacco smoke. 3,4-Benzopyrene,3,4-Benzpyrene,3,4 Benzopyrene,3,4 Benzpyrene
D050356 Lipid Metabolism Physiological processes in biosynthesis (anabolism) and degradation (catabolism) of LIPIDS. Metabolism, Lipid
D018336 Receptors, Aryl Hydrocarbon Cytoplasmic proteins that bind certain aryl hydrocarbons, translocate to the nucleus, and activate transcription of particular DNA segments. AH receptors are identified by their high-affinity binding to several carcinogenic or teratogenic environmental chemicals including polycyclic aromatic hydrocarbons found in cigarette smoke and smog, heterocyclic amines found in cooked foods, and halogenated hydrocarbons including dioxins and polychlorinated biphenyls. No endogenous ligand has been identified, but an unknown natural messenger with a role in cell differentiation and development is suspected. AH Receptors,Aryl Hydrocarbon Receptors,Dioxin Receptors,Receptors, AH,Receptors, Dioxin,TCDD Receptors,AH Receptor,Aryl Hydrocarbon Receptor,Dioxin Receptor,Polyaromatic Hydrocarbon Receptor,Polyaromatic Hydrocarbon Receptors,Receptors, 2,3,7,8-Tetrachlorodibenzo-p-dioxin,Receptors, Polyaromatic Hydrocarbon,Receptors, TCDD,TCDD Receptor,Receptor, AH,Receptor, Aryl Hydrocarbon,Receptor, Dioxin,Receptor, Polyaromatic Hydrocarbon,Receptor, TCDD

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