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

Prinetti, A., Cao, T., Illuzzi, G., Prioni, S., Aureli, M., Gagliano, N., et al. (2011). A glycosphingolipid/caveolin-1 signaling complex inhibits motility of human ovarian carcinoma cells. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 286(47), 40900-40910 [10.1074/jbc.M111.286146].

A glycosphingolipid/caveolin-1 signaling complex inhibits motility of human ovarian carcinoma cells

Prinetti, A
;
TREDICI, GIOVANNI;
2011

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
Articolo in rivista - Articolo scientifico
Cell Movement; Ovarian Neoplasms; Glucosyltransferases; Enzyme Activation; Gene Silencing; Humans; Tumor Microenvironment; Protein-Tyrosine Kinases; Caveolin 1; Cell Line, Tumor; Enzyme Inhibitors; Gangliosides; Protein Subunits; Integrins; Up-Regulation; Sialyltransferases; Signal Transduction; Female
English
2011
286
47
40900
40910
none
Prinetti, A., Cao, T., Illuzzi, G., Prioni, S., Aureli, M., Gagliano, N., et al. (2011). A glycosphingolipid/caveolin-1 signaling complex inhibits motility of human ovarian carcinoma cells. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 286(47), 40900-40910 [10.1074/jbc.M111.286146].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/45714
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