title: Ligand independent aryl hydrocarbon receptor inhibits lung cancer cell invasion by degradation of Smad4.
abstract: The aryl hydrocarbon receptor (AhR) is a ligand-dependent-activated transcriptional factor that regulates the metabolism of xenobiotic and endogenous compounds. Although AhR plays a crucial role in air toxicant-induced carcinogenesis, AhR expression was shown to negatively regulate tumorigenesis. Therefore, in the present study, we investigated the effect of AhR without ligand treatment on cancer invasion in lung cancer cell lines. Lung cancer cells expressing lower levels of AhR showed higher invasion ability (H1299 cells) compared with cells expressing higher levels of AhR (A549 cells). Overexpression of AhR in H1299 cells inhibited the invasion ability. We found that vimentin expression was inhibited in AhR-overexpressing H1299 cells. Additionally, the expression of EMT-related transcriptional factors Snail and ID-1 decreased. Interestingly, we found that Smad4 degradation was induced in AhR-overexpressing H1299 cells. Our data showed that AhR could interact with Jun-activation domain binding protein (Jab1) and Smad4, which may cause degradation of Smad4 by the proteasome. Our data suggest that AhR affects the transforming growth factor-β signaling pathway by inducing Smad4 degradation by the proteasome and suppressing tumor metastasis via epithelial to mesenchymal transition reduction in lung cancer cells.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, China Medicine University, Taichung, Taiwan.
authors.forename: Chen-Chen
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Yang
authors.affiliation: Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ching-Hao
authors.initials: CH
authors.lastname: Li
authors.affiliation: School of Pharmacy, Taipei Medicine University, Taipei, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Cheng
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: jjkang@ntu.edu.tw.
authors.forename: Jaw-Jou
authors.initials: JJ
authors.lastname: Kang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D000075686:COP9 Signalosome Complex; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D010447:Peptide Hydrolases / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D014162:Transfection; D054875:Ubiquitination; D014746:Vimentin / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000075686:COP9 Signalosome Complex; D051798:Inhibitor of Differentiation Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D018336:Receptors, Aryl Hydrocarbon; D051901:Smad4 Protein; D000071250:Snail Family Transcription Factors; D014746:Vimentin; C111235:AHR protein, human; C497453:ID1 protein, human; C497796:SMAD4 protein, human; C501488:COPS5 protein, human
keywords: Aryl hydrocarbon receptor; Epithelial to mesenchymal transition; Jun-activation domain binding protein; Lung cancer; Smad4; Transforming growth factor-β