Ganglioside GD1a inhibits HGF-induced motility and scattering of cancer cells through suppression of tyrosine phosphorylation of c-Met

Abstract

We previously reported that ganglioside GD1a, which is highly expressed in poorly metastatic FBJ-S1 cells, inhibits the serum-induced motility of FBJ-LL cells and that the metastatic potential of FBJ-LL cells is completely suppressed by enforced GD1a expression (Hyuga et al., Int J Cancer 1999; 83:685-91). We recently discovered that hepatocyte growth factor (HGF) induces FBJ-LL cell motility. In the present study, the HGF-induced motility of FBJ-S1 cells was found to be one-thirtieth that of FBJ-LL cells. This motility of GD1a-expressing transfectants, which were produced by transfection of FBJ-LL cells with GM2/GD2 synthase cDNA, decreased with increases in their GD1a expression and HGF induced almost no motility in GD1a-pretreated FBJ-LL cells, indicating that GD1a inhibits the HGF-induced motility of GD1a; HGF; motility; scattering Gangliosides are sialylated glycosphingolipids found on the outer layer of the plasma membrane. Changes in ganglioside expression in cancer cells are strongly related to their metastatic potential. 1-5 Although increases in complex ganglioside expression in cancer cells have been considered to be associated with malignancy, in our previous study we found that the poorly metastatic FBJ-S1 cells highly expressed the complex ganglioside GD1a, whereas the highly metastatic FBJ-LL cells only slightly expressed this ganglioside. 6 GD1a inhibited the serum-induced motility of FBJ-LL cells and the metastatic potential of FBJ-LL cells was completely suppressed by enforced GD1a expression. 7 It is possible that GD1a suppresses metastasis of FBJ-LL cells by inhibiting cell migration. The target molecules of GD1a need to be identified to clarify the mechanism of inhibition of metastasis by GD1a. Key words:We recently found that HGF induces FBJ-LL cell motility 8 and that the serum-induced motility of FBJ-LL cells was decreased by treatment of the serum with anti-HGF antibody (unpublished data), suggesting that HGF is a migration-stimulating factor in serum. Since FBJ-LL cells metastasize to the liver and HGF is secreted by nonparenchymal liver cells, HGF may promote liver metastasis of FBJ-LL cells. We suspect that HGF may play a key role in FBJ-LL cell metastasis. HGF is a multipotential modulator of biologic activities in a variety of cell types and it influences the growth, motility, differentiation and morphogenesis of its target cells through the c-Met tyrosine kinase receptor. 9 HGF has been described as a potent chemotactic factor 10 and has been associated with the progression of carcinoma cells. 11 Overexpression of the HGF receptor, c-Met, in malignant cells has been reported in various tissues. 12 Hence HGF may play a crucial role in cancer metastasis.In the present study, we attempted to identify the target molecules of GD1a by analyzing the molecular mechanism of the inhibition of cell migration by GD1a. We found that GD1a inhibited the HGFinduced motility, morphologic change and formation of actin stress fibers in FBJ-LL cells through suppression of tyrosine phosphorylation ...

Relationship between ganglioside GD1a and inflammatory response in the coculture of human endothelial cells with porcine endothelial cells

“…Several studies have reported that exposure to gangliosides can induce the production of various inflammatory mediators such as cytokines (Blennow et al 1991). Ganglioside GD1a has been reported to suppress FBJ cells growth (Hyuga et al 2001). Our find the GD1a expression and synthase was increased in cocultured cells were increased the inflammatory factors such as TNF-α, p65, and p 50.…”

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

“…Previously, it has been shown that a-series gangliosides act as negative regulators of c-Met. G D1a inhibits HGF-induced motility and scattering of cancer cells through suppression of tyrosine phosphorylation of c-Met (33). G M3 and G M2 form heterodimers that specifically interact with tetraspanin (CD82) in glycosynapses, and such complexes inhibit c-Met activation and integrin cross talk (34,35).…”

Ganglioside GD1a regulation of caveolin-1 and Stim1 expression in mouse FBJ cells:Augmented expression of caveolin-1 and Stim1 in cells with increased GD1a content

“…LA5-22 cells showed no indication of metastasis in mice to whose thighs these cells had been administered and which were sacrificed at 4 to 5 weeks to confirm the presence of tumor cells in organs macroand microscopically. M5 cells as a control mock transfectant were found to have metastasized to lung, liver and kidney [2]. GD1a is thus shown to control the metastatic machinery of FBJ cells but the underlying mechanism for this remains to be clarified.…”

“…Ganglioside GD1a regulates cell motility, cell adhesiveness to vitronectin, phosporylation of c-Met and metastatic capacity of mouse FBJ cell lines [1][2][3]. Using cells derived from FBJ-virus-induced mouse osteosarcoma, FBJ-S1 cells with no indication of metastasis were found to express gangliosides GM3 and GD1a, whereas FBJ-LL cells, capable of mestasizing to lung and liver subsequent to subcutaneous transplantation of cells to mouse thigh, possessed GM3 and GD1a but the latter in only limited amounts.…”