title: The mechanism and significance of synergistic induction of the expression of plasminogen activator inhibitor-1 by glucocorticoid and transforming growth factor beta in human ovarian cancer cells.
abstract: Plasminogen activator inhibitor-1 (PAI-1) plays a key role in tissue remodeling and tumor development by suppression of plasminogen activator function. Glucocorticoids (GCs) and transforming growth factor beta (TGF-β) signal pathways cross-talk to regulate gene expression, but the mechanism is poorly understood. Here we investigated the mechanism and significance of co-regulation of PAI-1 by TGF-β and dexamethasone (DEX), a synthetic glucocorticoid in ovarian cancer cells. We found that TGF-β and DEX showed rapidly synergistic induction of PAI-1 expression, which contributed to the early pro-adhesion effects. The synergistic induction effect was accomplished by several signal pathways, including GC receptor (GR) pathway and TGF-β-activated p38MAPK, ERK and Smad3 pathways. TGF-β-activated p38MAPK and ERK pathways cross-talked with GR pathway to augment the expression of PAI-1 through enhancing DEX-induced GR phosphorylation at Ser211 in ovarian cancer cells. These findings reveal possible novel mechanisms by which TGF-β pathways cooperatively cross-talk with GR pathway to regulate gene expression.
authors.affiliation: Department of Endocrinology, Shanghai 10th People's Hospital, Tongji University, Shanghai 200072, China.
authors.forename: Xiao-yu
authors.initials: XY
authors.lastname: Pan
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
authors.forename: Gao-xiang
authors.initials: GX
authors.lastname: Huang
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
authors.forename: Dong-mei
authors.initials: DM
authors.lastname: Cao
authors.affiliation: Department of Endocrinology, Shanghai 10th People's Hospital, Tongji University, Shanghai 200072, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Qu
authors.affiliation: Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. Electronic address: lujian326@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D011965:Receptors, Glucocorticoid; C051321:SERPINE1 protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D003907:Dexamethasone; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Dexamethasone; Ovarian cancer; Phosphorylation; Plasminogen activator inhibitor-1; Transforming growth factor beta