title: Activation of G-Protein-Coupled Estrogen Receptor Inhibits the Migration of Human Nonsmall Cell Lung Cancer Cells via IKK-β/NF-κB Signals.
abstract: Estrogen signals have been suggested to modulate the progression and metastasis of nonsmall cell lung cancer (NSCLC), which is one of the leading causes of cancer deaths worldwide. While there are limited data concerning the roles and effects of G-protein-coupled estrogen receptor (GPER) on the progression of NSCLC, our present study reveals that the expression of GPER in NSCLC cells is obviously greater than that in lung fibroblast cell line MRC-5. Activation of GPER via its specific agonist G-1 decreases the in vitro motility of A549 and H358 cells and the expression of matrix metalloproteinase 2 (MMP-2) and MMP-9. Further, G-1 treatment can rapidly decrease the phosphorylation, nuclear translocation, and promoter activities of NF-κB in NSCLC cells. BAY 11-7082, the inhibitor of NF-κB, also inhibits the expression of MMP-2/9, while overexpression of p65 significantly attenuates G-1-induced downregulation of MMP-2/9. It suggests that inhibition of NF-κB mediates G-1-induced MMP-2/9 downregulation. G-1 treatment significantly down regulates the phosphorylation of IκB kinase β (IKK-β) and IκBα, while not IKK-α, in both 549 and H358 cells. ACHP, the specific inhibitor of IKK-β, can reinforce G-1-induced MMP-2/9 downregulation and invasion suppression of A549 cells. Collectively, our results suggest that activation of GPER can inhibit the migration of human NSCLC cells via suppression of IKK-β/NF-κB signals. These findings will help to better understand the roles and mechanisms of GPER as a potential therapy target for NSCLC patients.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University , Beijing, People's Republic of China .
authors.forename: Guangfa
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University , Beijing, People's Republic of China .
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University , Beijing, People's Republic of China .
authors.forename: Chunting
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University , Beijing, People's Republic of China .
authors.forename: Dong
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University , Beijing, People's Republic of China .
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Shi
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003517:Cyclopentanes / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D009928:Organ Specificity; D011804:Quinolines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; C501280:2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-piperidin-4-yl nicotinonitrile; C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D003517:Cyclopentanes; C109584:GPER1 protein, human; D016328:NF-kappa B; D009539:Nicotinic Acids; D009570:Nitriles; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9