Changes in glycosylation is a common feature of cancer cells that affects both
N- and
O-glycosylproteins as well as glycophingolipids, leading to the expression of tumor-associated carbohydrate antigens (TACA). These changes in glycosylation are usually explained by changes in the expression of specific glycosyltransferases, and are associated with increased aggressiveness of the tumors and a poor prognosis for the patients
[1]. Gangliosides constitute a subclass of glycophingolipids substituted by one or more sialic acid residues. In humans, sialic acid molecules are exclusively
N-acetyl-neuraminic acids (Neu5Ac) that can be
O-acetylated, mainly on C9
[2]. Gangliosides are essential compounds of the plasma membrane, notably expressed at the outer leaflet in microdomains named “glycosynapses”, where they interact with cholesterol, phospholipids, transmembrane receptors, and signal transducers, controlling carbohydrate-dependent cell adhesion and signaling
[3]. Normal human tissues mainly express mono-sialyl gangliosides, such as GM3 or GM1a; alternatively, di- or tri-sialyl gangliosides, with two or three sialic acid residues linked to the Gal residue of lactosylceramide (LacCer-Gg
2Cer), are essentially found in developing tissues, during embryogenesis, and are mainly restricted to the nervous system in healthy adults
[4]. Within glycosynapses, gangliosides are important regulators of receptor tyrosine kinases (RTK), and therefore play major roles in cell proliferation, adhesion, and motility
[5]. Basically, mono-sialyl gangliosides are usually considered as downregulators of RTK signaling, whereas di-sialyl gangliosides upregulate RTK activation and downstream signaling pathways
[6]. In mammals, the expression of b- and c-series gangliosides increases under pathological conditions, including cancers
[7]. Particularly, di-sialyl gangliosides GD3 and GD2 have been described as TACA in neuroectoderm-derived tumors, including melanoma, neuroblastoma, and glioblastoma, as well as in breast cancer
[8]. Moreover, substantial evidence has demonstrated the implication of complex gangliosides in oncogenesis by mediating cell proliferation, migration, stemness, tumor growth, and angiogenesis, making di-sialyl gangliosides interesting therapeutic targets for cancer immunotherapy
[9]. The overexpression of complex gangliosides in cancers is usually correlated with the upregulation of
ST8SIA1 gene expression, which encodes the key enzyme for complex ganglioside synthesis, GD3 synthase (CMP-
N-acetylneuraminate, GM3 α2,8-sialyltransferase, or ST8Sia I, EC 2.4.99.8, GD3S). Despite the role of GD2 synthase (encoded by the
B4GALNT1 gene) as the enzyme directly responsible for GD2 synthesis, GD3S is the rate-limiting enzyme of GD2 biosynthesis in breast cancer stem cells that have undergone epithelial–mesenchymal transition (EMT). In breast cancer stem cells, GD2 is considered as the ganglioside responsible for cancer cell stemness and metastatic properties, and various immunotherapy strategies targeting GD2 are used, or in development, for numerous cancer types
[10][11]. However, since GD2 synthesis depends on GD3S expression levels, targeting GD3S could be a valuable therapeutic approach, in combination with these conventional therapies.