Physiological concentrations of gangliosides GM1, GM2 and GM3 differentially modify basic-fibroblast-growth-factor-induced mitogenesis and the associated signalling pathway in endothelial cells.
It has been suggested that gangliosides can influence the growth of cells by modulation of growth-factor-receptor signalling. The activation of endothelial cells (EC) during angiogenesis is crucial for tumour growth and for metastasis, also for numerous other physiological and pathological situations. Pre-treatment of bovine aortic endothelial cells (BAEC) with GM1 or GM2 (5-20 microM) inhibited basic-fibroblast-growth-factor (bFGF)-induced mitogenesis, but GM3 (0.1-20 microM) acted synergistically, increasing proliferation above that of bFGF alone (p < 0.05). The mitogenic effect of all 3 gangliosides was markedly reduced if the cells were washed to remove excess gangliosides from the medium before addition of bFGF. We further show that GM1 and to a lesser extent GM2 modify bFGF binding to its receptor and inhibit the associated mitogenic signal-transduction pathway of protein-tyrosine phosphorylation of 40 to 120 kDa, PLCgamma1, MAP kinase and protein-kinase-C activation. In contrast, GM3 increased tyrosine phosphorylation and MAP kinase activity, as compared with bFGF alone. The observed differential modulation of bFGF-induced mitogenesis by GM1, GM2 and GM3 was at concentrations routinely occurring in the serum of cancer patients. The results suggest that circulating gangliosides may have a role in regulating solid-tumour growth by modulating angiogenesis.
Slevin
M
M
Department of Biological Sciences, Manchester Metropolitan University, England. M.A.Slevin@MMU.ac.uk
Kumar
S
S
He
X
X
Gaffney
J
J
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D005677:G(M1) Ganglioside / Q000502:physiology*; D005678:G(M2) Ganglioside / Q000502:physiology*; D005679:G(M3) Ganglioside / Q000502:physiology*; D007527:Isoenzymes / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology*; D051966:Phospholipase C gamma; D011493:Protein Kinase C / Q000187:drug effects; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D010738:Type C Phospholipases / Q000187:drug effects
D005679:G(M3) Ganglioside; D007527:Isoenzymes; D008934:Mitogens; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D005678:G(M2) Ganglioside; D005677:G(M1) Ganglioside; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma