Gangliosides as Signaling Regulators in Cancer

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.

Keywords: cancer; ganglioside; receptor; signaling.

Figure 1

Schematic diagram of major GSL pathways, including gangliosides synthesis glycosyltransferases (ST3GAL5, ST8SIA1, B4GALNT1, B3GALT4, and ST3GAL2). Pathways of the major gangliosides (a-series and b-series) mentioned in this review are shown within the red dotted rectangles. GSL, glycosphingolipids; Glc, glucose; Gal, galactose; GalNAc, N-acetylgalactosamine; Neu5Ac, N-acetylneuraminic acid; GlcCer, glucosylceramide; LacCer, lactosylceramide.

Figure 2

Each species of cancer in the human body and related gangliosides as described in this text.

Figure 3

The effects of gangliosides on cancer cell signaling. Gangliosides usually form complexes with several types of RTK receptors in lipid rafts of cancer cells. These interactions contribute to the activation or inhibition of RTK signaling, leading to suppression or promotion of malignant properties in cancer cells. RTK, receptor tyrosine kinase.

Figure 4

Three possible ganglioside-targeting strategies for cancer therapy. (A,B) Treatment with glucosylceramide synthase inhibitors such as AMP-dNM or specific inhibitors of GM3 synthase reduces glycans in gangliosides (A). Furthermore, treatment with an inhibitor of glycosyltransferases, or inducers or siRNA of glycosyltransferase or NEU3 reduces glycans in gangliosides (B). This affects the interaction of glycan-reduced gangliosides and receptors, activating or inhibiting signal, reducing malignancy. (C) Treatment with ganglioside-specific antibody contributes to attenuation of signal transduction or activation of apoptotic pathways, leading to reduced malignancy.