title: A glycosphingolipid/caveolin-1 signaling complex inhibits motility of human ovarian carcinoma cells.
abstract: The genetic (stable overexpression of sialyltransferase I, GM3 synthase) or pharmacological (selective pressure by N-(4-hydroxyphenyl)retinamide)) manipulation of A2780 human ovarian cancer cells allowed us to obtain clones characterized by higher GM3 synthase activity compared with wild-type cells. Clones with high GM3 synthase expression had elevated ganglioside levels, reduced in vitro cell motility, and enhanced expression of the membrane adaptor protein caveolin-1 with respect to wild-type cells. In high GM3 synthase-expressing clones, both depletion of gangliosides by treatment with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol and silencing of caveolin-1 by siRNA were able to strongly increase in vitro cell motility. The motility of wild-type, low GM3 synthase-expressing cells was reduced in the presence of a Src inhibitor, and treatment of these cells with exogenous gangliosides, able to reduce their in vitro motility, inactivated c-Src kinase. Conversely, ganglioside depletion by D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol treatment or caveolin-1 silencing in high GM3 synthase-expressing cells led to c-Src kinase activation. In high GM3 synthase-expressing cells, caveolin-1 was associated with sphingolipids, integrin receptor subunits, p130(CAS), and c-Src forming a Triton X-100-insoluble noncaveolar signaling complex. These data suggest a role for gangliosides in regulating tumor cell motility by affecting the function of a signaling complex organized by caveolin-1, responsible for Src inactivation downstream to integrin receptors, and imply that GM3 synthase is a key target for the regulation of cell motility in human ovarian carcinoma.
authors.affiliation: Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, 20090 Segrate, Italy. alessandro.prinetti@unimi.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prinetti
authors.forename: Ting
authors.initials: T
authors.lastname: Cao
authors.forename: Giuditta
authors.initials: G
authors.lastname: Illuzzi
authors.forename: Simona
authors.initials: S
authors.lastname: Prioni
authors.forename: Massimo
authors.initials: M
authors.lastname: Aureli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Gagliano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tredici
authors.forename: Virginia
authors.initials: V
authors.lastname: Rodriguez-Menendez
authors.forename: Vanna
authors.initials: V
authors.lastname: Chigorno
authors.forename: Sandro
authors.initials: S
authors.lastname: Sonnino
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005732:Gangliosides / Q000378:metabolism*; D020868:Gene Silencing; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D016023:Integrins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D021122:Protein Subunits / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059016:Tumor Microenvironment / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D019061:src-Family Kinases
chemical_list: D051242:Caveolin 1; D004791:Enzyme Inhibitors; D005732:Gangliosides; D016023:Integrins; D021122:Protein Subunits; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D012799:Sialyltransferases; C021343:haematoside synthetase; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human