title: Increased expression of matrix metalloproteinases mediates thromboxane A2-induced invasion in lung cancer cells.
abstract: Thromboxane A(2) receptor (TP) has been shown to play an important role in multiple aspects of cancer development including regulation of tumor growth, survival and metastasis. Here we report that TP mediates cancer cell invasion by inducing expression of matrix metalloproteinases (MMPs). TP agonist, I-BOP, significantly elevated MMP-1, MMP-3, MMP-9 and MMP-10 mRNA levels in A549 human lung adenocarcinoma cells overexpressing TPα or TPβ. The secretion of MMP-1 and MMP-9 in conditioned media was determined using Western blot analysis and zymographic assay. Signaling pathways of I-BOP-induced MMP-1 expression were examined in further detail as a model system for MMPs induction. Signaling molecules involved in I-BOP-induced MMP-1 expression were identified by using specific inhibitors including small interfering (si)-RNAs of signaling molecules and promoter reporter assay. The results indicate that I-BOP-induced MMP-1 expression is mediated by protein kinase C (PKC), extracellular signal-regulated kinase (ERK)-activator protein-1(AP-1) and ERK-CCAAT/enhancer-binding protein β (C/EBPβ) pathways. I-BOP-induced cellular invasiveness of A549 cells expressing TPα or TPβ was determined by invasion assay. GM6001, a general inhibitor of MMPs, decreased basal and I-BOP-induced cell invasion. Knockdown of MMP-1 and MMP-9 by their respective siRNA partially reduced I-BOP-stimulated cell invasion suggesting that other MMPs induced by I-BOP were also involved. Our studies establish the relationship between TP and MMPs in cancer cell invasion and suggest that the thromboxane A(2) (TXA(2))-TP signaling is a potential therapeutic target for cancer invasion and metastasis.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, 40536-0596, USA.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Li
authors.forename: Hsin-Hsiung
authors.initials: HH
authors.lastname: Tai
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011480:Protease Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D022782:CCAAT-Enhancer-Binding Protein-beta; D004151:Dipeptides; D005231:Fatty Acids, Unsaturated; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D012333:RNA, Messenger; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D018808:Transcription Factor AP-1; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D013928:Thromboxane A2; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1