title: Cell surface syndecan-1 contributes to binding and function of macrophage migration inhibitory factor (MIF) on epithelial tumor cells.
abstract: Surface expressed proteoglycans mediate the binding of cytokines and chemokines to the cell surface and promote migration of various tumor cell types including epithelial tumor cells. We here demonstrate that binding of the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) to epithelial lung and breast tumor cell lines A549 and MDA-MB231 is sensitive to enzymatic digestion of heparan sulphate chains and competitive inhibition with heparin. Moreover, MIF interaction with heparin was confirmed by chromatography and a structural comparison indicated a possible heparin binding site. These results suggested that proteoglycans carrying heparan sulphate chains are involved in MIF binding. Using shRNA-mediated gene silencing, we identified syndecan-1 as the predominant proteoglycan required for the interaction with MIF. MIF binding was decreased by induction of proteolytic shedding of syndecan-1, which could be prevented by inhibition of the metalloproteinases involved in this process. Finally, MIF induced the chemotactic migration of A549 cells, wound closure and invasion into matrigel without affecting cell proliferation. These MIF-induced responses were abrogated by heparin or by silencing of syndecan-1. Thus, our study indicates that syndecan-1 on epithelial tumor cells promotes MIF binding and MIF-mediated cell migration. This may represent a relevant mechanism through which MIF enhances tumor cell motility and metastasis.
authors: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors: Tobias
authors: T
authors: Pasqualon
authors: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University Aachen, Germany.
authors: Hongqi
authors: H
authors: Lue
authors: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University Aachen, Germany; Department of Anesthesiology, RWTH Aachen University, Aachen, Germany.
authors: Sabine
authors: S
authors: Groening
authors: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors: Jessica
authors: J
authors: Pruessmeyer
authors: Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany.
authors: Holger
authors: H
authors: Jahr
authors: Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany.
authors: Bernd
authors: B
authors: Denecke
authors: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University Aachen, Germany; Chair of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors: Jürgen
authors: J
authors: Bernhagen
authors: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany. Electronic address: aludwig@ukaachen.de.
authors: Andreas
authors: A
authors: Ludwig
mesh_terms: D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism* / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism* / Q000502:physiology*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D053668:Syndecan-1 / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D006497:Heparan Sulfate; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D053668:Syndecan-1; C515598:MIF protein, human
keywords: Chemokine; Heparin; Macrophage migration inhibitory factor; Metalloproteinase; Proteoglycan; Syndecan; Tumor cell migration