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.
A glycosphingolipid/caveolin-1 Signaling Complex Inhibits Motility of Human Ovarian Carcinoma Cells / A. Prinetti, T. Cao, G. Illuzzi, S. Prioni, M. Aureli, N. Gagliano, G. Tredici, V. Rodriguez-Mendez, V. Chigorno, S. Sonnino. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 286:47(2011 Nov 25), pp. 40900-40910.
|Titolo:||A glycosphingolipid/caveolin-1 Signaling Complex Inhibits Motility of Human Ovarian Carcinoma Cells|
CAO, TING (Secondo)
CHIGORNO, VANNA LUIGIA (Penultimo)
SONNINO, SANDRO (Ultimo)
|Parole Chiave:||ENRICHED MEMBRANE DOMAINS ; RAT CEREBELLAR NEURONS ; BLADDER-CANCER CELLS ; GM3 GANGLIOSIDE ; TYROSINE KINASE ; PRION PROTEIN ; ACTIVE SRC ; CAVEOLIN-1 ; TUMOR ; EXPRESSION|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Data di pubblicazione:||25-nov-2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1074/jbc.M111.286146|
|Appare nelle tipologie:||01 - Articolo su periodico|