| Research Abstract |
In this project, we have tried to investigate roles of glycosphingolipids expressed on cancer cells and neuronal cells in the regulation of biosignals, and to clarify mechanisms for the pathogenesis due to their abnormalities. In order to achieve these aims, we analysed ; 1. regulatory mechanisms of signaling with glycilipids in melanomas and small cell lung cancers based on the remodeling of glycosylation patterns, 2. establishment and analysis of abnormal phenotypes of gene knockout mice of glycosyltransferases to elucidate roles of glycolipids in vivo. In melanoma cells, characteristic expression of GD3 induced enhancement of tyrosine phosphorylation of adaptor molecules such as p130Cas and paxillin, and increased cell growth and invasion activity. Furthermore, focal adhesion kinase (FAK) was also activated more strongly in GD3+ cells than in GD3- cells. On the other hand, GD2 expression resulted in the enhancement of cell proliferation and invasion in small cell lung cancer cells,
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and binding of anti-GD2 antibodies could trigger apoptosis of small cell lung cancer cells. It was, then, demonstrated that anti-GD2 antibodies could induce dephosphorylation of FAK and activation of p38, leading to anoikis. Consequently, it was concluded that anti-GD2 antibodies trigger anoikis, and it was essential to destroy molecular complex sonsisting of GD2. Integrin and FAK as an efficient strategy toward cancer therapeutics.
As for roles of glycosphingolipids in nervous tissues, it has been suspected that acidic glycosphingolipids paly important roles in the development and function of nervous systems based on their high levels of expression. In order to clarify their roles in the nervous tissues, we generated gene knockout mice lines, i. e. knockout mice of GM2/GD2 synthase, GD3 synthase, double knockout of those two, GM3 synthase, and lactosylceramide synthase. As results of phenotypic analyses of these mutant mice, we have demonstrated that they showed abnormal phenotypic changes according to the range of defects in ganglioside structures. Generally, acidic glycolipids appeared to be essential in the maintenance of the integrity of the nervous tissues and repair after neuronal damages. Furthermore, comparison of gene expression profiles in the nerve tissues between wild type and double knockout mice revealed that neurodegeneration detected in the mutant mice are not mere atrophic changes, but active changes with inflammatory process as indicated by the activation of complementary system and cytokine production or secretion. Less
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