title: Hyaluronan cell surface binding is induced by type I collagen and regulated by caveolae in glioma cells.
abstract: Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesterol-depleting agent beta-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies.
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Chemistry Department, Université du Québec à Montréal.
authors.forename: Borhane
authors.initials: B
authors.lastname: Annabi
authors.forename: Sébastien
authors.initials: S
authors.lastname: Thibeault
authors.forename: Robert
authors.initials: R
authors.lastname: Moumdjian
authors.forename: Richard
authors.initials: R
authors.lastname: Béliveau
mesh_terms: D021941:Caveolae / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D024042:Collagen Type I / Q000737:chemistry*; D004396:Coloring Agents / Q000494:pharmacology; D003505:Cyclodextrins / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D006820:Hyaluronic Acid / Q000378:metabolism*; D006877:Hydroxamic Acids; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D008954:Models, Biological; D017830:Octoxynol / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D014162:Transfection; D015854:Up-Regulation; D047392:beta-Cyclodextrins
chemical_list: D024042:Collagen Type I; D004396:Coloring Agents; D003505:Cyclodextrins; D018076:DNA, Complementary; D003902:Detergents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018960:Hyaluronan Receptors; D006877:Hydroxamic Acids; D007211:Indoles; D011994:Recombinant Proteins; D047392:beta-Cyclodextrins; D012313:RNA; D017830:Octoxynol; D006820:Hyaluronic Acid; D002784:Cholesterol; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C119203:ilomastat; D016650:Fluorescein-5-isothiocyanate; C031215:betadex; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one