Abstract
At the plasma membrane, gangliosides, a group of glycosphingolipids, are expressed along with glycosphingolipids, phospholipids, and cholesterol in so-called lipid rafts that interact with signaling receptors and related molecules. Most cancers present abnormalities in the intracellular signal transduction system involved in tumor growth, invasion, and metastasis. To date, the roles of gangliosides as regulators of signal transduction have been reported in several cancer types. Gangliosides can be expressed by the exogenous ganglioside addition, with their endogenous expression regulated at the enzymatic level by targeting specific glycosyltransferases. Accordingly, the relationship between changes in the composition of cell surface gangliosides and signal transduction has been investigated by controlling ganglioside expression. In cancer cells, several types of signaling molecules are positively or negatively regulated by ganglioside expression levels, promoting malignant properties. Moreover, antibodies against gangliosides have been shown to possess cytotoxic effects on ganglioside-expressing cancer cells. In the present review, we highlight the involvement of gangliosides in the regulation of cancer cell signaling, and we explore possible therapies targeting ganglioside-expressing cancer.
Highlights
Gangliosides are a group of acidic glycosphingolipids (GSLs) possessing one or more sialic acid residues on their carbohydrate moieties, mainly located in sphingolipid and cholesterol-enriched domains called lipid rafts
Recent studies have shown that pancreatic cancer is a morphologically and functionally heterogeneous tumor, possessing epithelial-to-mesenchymal features, and Transforming growth factor (TGF)-β contributes to the epithelial–mesenchymal transition (EMT) features of pancreatic cancer cells [51,52]
We reported that a glucosylceramide synthase inhibitor, N(5-adamantane-1-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-dNM), reduced TGF-β1 signaling, presumably by inhibiting the interaction between GM2 and TGFβ receptor II by downregulating GM2, resulting in suppression of invasion in cancer stem cell (CSC)-like
Summary
Gangliosides are a group of acidic glycosphingolipids (GSLs) possessing one or more sialic acid residues on their carbohydrate moieties, mainly located in sphingolipid and cholesterol-enriched domains called lipid rafts. Receptor tyrosine kinases (RTKs) are activated afterdomain; ligand binding, inducing ing receptor dimerization and autophosphorylation of the kinase this results in receptor dimerization autophosphorylation of the cell kinase domain; this resultsdifin the the activation of diverseand signaling cascades that regulate survival, proliferation, ferentiation, and invasion in various types ofcell cancer. Changes gangliosides are subtle regulators of RTK signaling [9], and that changes in the composiin ganglioside expression at the plasma membrane modify the molecular composition and in tion of cancer cell surface gangliosides affect cellular responses [2,6]. We highlight the role of gangliosides in cancer cell signaling, including cell growth and apoptosis, and discuss their potential as therapeutic targets for cancer
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