title: Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress.
abstract: Environmental cigarette smoke has been suggested to promote lung adenocarcinoma progression through aryl hydrocarbon receptor (AhR)-signaled metabolism. However, whether AhR facilitates metabolic activation or detoxification in exposed adenocarcinoma cells remains ambiguous. To address this question, we have modified the expression level of AhR in two human lung adenocarcinoma cell lines and examined their response to an extract of cigarette sidestream smoke particulates (CSSP). We found that overexpression of AhR in the CL1-5 cell line reduced CSSP-induced ROS production and oxidative DNA damage, whereas knockdown of AhR expression increased ROS level in CSSP-exposed H1355 cells. Oxidative stress sensor Nrf2 and its target gene NQO1 were insensitive to AhR expression level and CSSP treatment in human lung adenocarcinoma cells. In contrast, induction of AhR expression concurrently increased mRNA expression of xenobiotic-metabolizing genes CYP1B1, UGT1A8, and UGT1A10 in a ligand-independent manner. It appeared that AhR accelerated xenobiotic clearing and diminished associated oxidative stress by coordinate regulation of a set of phase I and II metabolizing genes. However, the AhR-signaled protection could not shield cells from constant oxidative stress. Prolonged exposure to high concentrations of CSSP induced G0/G1 cell cycle arrest via the p53-p21-Rb1 signaling pathway. Despite no effect on DNA repair rate, AhR facilitated the recovery of cells from growth arrest when CSSP exposure ended. AhR-overexpressing lung adenocarcinoma cells exhibited an increased anchorage-dependent and independent proliferation when recovery from exposure. In summary, our data demonstrated that AhR protected lung adenocarcinoma cells against CSSP-induced oxidative stress and promoted post-exposure clonogenicity.
authors.affiliation: Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung 40402, Taiwan, ROC.
authors.forename: Ya-Hsin
authors.initials: YH
authors.lastname: Cheng
authors.forename: Su-Chin
authors.initials: SC
authors.lastname: Huang
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Lin
authors.forename: Li-Chuan
authors.initials: LC
authors.lastname: Cheng
authors.forename: Lih-Ann
authors.initials: LA
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D065633:Cytochrome P-450 CYP1B1; D004249:DNA Damage / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D012906:Smoke; D014028:Tobacco Smoke Pollution; D015262:Xenobiotics; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; D014453:Glucuronosyltransferase; C454320:UDP-glucuronosyltransferase, UGT1A8