期刊
CELL PROLIFERATION
卷 35, 期 2, 页码 105-115出版社
BLACKWELL PUBLISHING LTD
DOI: 10.1046/j.1365-2184.2002.00228.x
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The inhibitory action of gangliosides GT(1B), GD(1A) GM(3) and GM, on cell proliferation and epidermal growth factor receptor (EGFR) phosphorylation was determined in the N-myc amplified human neuroblastoma cell line NBL-W. The IC50 of each ganglioside was estimated from concentration-response regressions generated by incubating NBL-W cells with incremental concentrations (5-1000 mum) of GT(1B), GD(1A) GM(3) or GM(1) for 4 days. Cell proliferation was quantitatively determined by a colourimetric assay using tetrazolium dye and spectrophotometric analysis, and EGFR phosphorylation by densitometry of Western blots. All gangliosides assayed, with the exception of GM(1), inhibited NBL-W cell proliferation in a concentration-dependent manner. The IC50s for gangliosides GT(1B) [molecular weight (MW) 2129], GM(3) (MW 1236), and GD(1A) (MW 1838) were (mean +/- SEM) 117 +/- 26, 255 +/- 29, and 425 +/- 44 m, respectively. In contrast, the IC50 for GM(1) (MW 1547) could not be determined. Incubation of NBL-W cells with epidermal growth factor (EGF) concentrations ranging from 0.1 to 1000 ng/ml progressively increased cell proliferation rate, but it plateaued at concentrations above 10 ng/ml. EGFR tyrosine phosphorylation, however, was incrementally stimulated by EGF concentrations from 1 to 100 ng/ml. The suppression of EGF-induced EGFR phosphorylation differed for each ganglioside, and their respective inhibitory potencies were as follows: EGFR phosphorylation [area under curve (+ EGF)/area under curve (- EGF)]: control (no ganglioside added) = 8.2; GM(1) = 8.3; GD(1A) = 6.7; GM(3) = 4.87, and GT(1B) = 4.09. The lower the ratio, the greater the inhibitory activity of the ganglioside. Gangliosides GD(1A) and GT(1B) which have terminal N-acetyl neuraminic acid moieties, as well as one and two N-acetyl neuraminic acid residues linked to the internal galactose, respectively, both inhibited cell proliferation and EGFR phosphorylation. However, GD(1A) was a more potent suppressor of cell proliferation and GT(1B) most effective against EGFR phosphorylation. GM(3), which only has a terminal N-acetyl neuraminic acid, inhibited cell proliferation and EGFR phosphorylation almost equivalently. These data suggest that gangliosides differ in their potency as inhibitors of NBL-W neuroblastoma cell proliferation and EGFR tyrosine phosphorylation, and that perturbations in the differential expression of membrane glycosphingolipids may play a role in modulating neuroblastoma growth.
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