Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

Abstract

Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides). The current strategies in the battle against cancer in which glycolipids are key players are then described.

Monoclonal Antibodies Targeting LecLex-Related Glycans with Potent Antitumor Activity

“…Control wells, consisted of cells incubated without conjugate, incubated with secondary Fab-ZAP without primary mAb and incubated with a control mAb in the presence of Fab-ZAP. Cell viability was measured by 3 H-thymidine incorporation during the final 24 hours. Results are expressed as a percentage of 3 H-thymidine incorporation by cells incubated with conjugate compared with primary mAb only.…”

“…The complexity of the glycome and altered expression of glycosyl transferases associated with malignant transformation make cancer cell-associated carbohydrates excellent targets (1)(2)(3)(4). Glycolipids are particularly attractive due to their dense cell-surface distribution, mobility, and association with membrane microdomains, all of which contribute to their participation in a wide range of cellular signaling and adhesion processes (4)(5)(6).…”

De novo expression of human polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6) in colon adenocarcinoma inhibits the differentiation of colonic epithelium

“…Malignant transformation is closely associated with changes in the glycosylation of proteins and lipids (1,2). One well-documented example, which is observed in the majority of epithelial cancers and premalignant lesions, is cancer-associated changesinGalNAcO-glycosylation (1,(3)(4)(5).GalNAc-typeO-glycosylation is an abundant and diverse form of post-translational modification (6).…”

“…One well-documented example, which is observed in the majority of epithelial cancers and premalignant lesions, is cancer-associated changesinGalNAcO-glycosylation (1,(3)(4)(5).GalNAc-typeO-glycosylation is an abundant and diverse form of post-translational modification (6). It is initiated by a family of up to 20 polypeptides, termed GalNAc-transferases (GalNAc-Ts), 2 that catalyzes the addition of GalNAc residues to the hydroxyl groups of selected serine and threonine residues in proteins (6 -19). In healthy cells, the initiating GalNAc residue (GalNAc␣1, also known as the Tn antigen) is elongated, branched, and capped with different carbohydrate structures in sequential processing steps.…”

Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase

“…Gangliosides are sialic acid-containing glycosphingolipids that are enriched in glycolipid-enriched microdomain (GEM) 2 / rafts on the plasma membrane of cells (1,2). Normal adult brain tissues express gangliosides GM1, GD1a, GD1b, and GT1b as major components and express minimal levels of GD3 and GD2 (3,4).…”