Bittersweet Sugars: How Unusual Glycan Structures May Connect Epithelial-to-Mesenchymal Transition and Multidrug Resistance in Cancer

Abstract

Cancer cells are characterized by metabolic reprogramming, which enables their survival in of-ten inhospitable conditions. A very well-documented example that has gained attraction in re-cent years and is already considered a hallmark of transformed cells is the reprogramming of carbohydrate metabolism. Such a feature, in association with the differential expression of en-zymes involved in the biosynthesis of glycoconjugates, generically known as glycosyltransfer-ases, contributes to the expression of structurally atypical glycans when compared to those ex-pressed in healthy tissues. The latest studies have demonstrated that glycophenotypic alterations are capable of modulating multifactorial events essential for the development and/or progres-sion of the disease. Herein, we will address the importance of glycobiology in modern medi-cine, focusing on the ability of unusual/truncated O-linked glycans to modulate two complex and essential phenomena for cancer progression: the acquisition of the multidrug resistance (MDR) phenotype and the activation of molecular pathways associated with the epithelial-mesenchymal transition (EMT) process, an event deeply linked with cancer metastasis.

Keywords: cancer; epithelial–mesenchymal transition process; glycoconjugates; glycosyltransferases; multidrug resistance phenotype.

Figure 1

Tn, sialyl Tn and T antigens are the main examples of truncated O-linked glycans expressed in cancer cells. O-glycosylation is usually initiated in the Golgi apparatus, where C1GALT1, also known as T-synthase, adds galactose (Gal) from UDP-Gal to the common precursor Tn antigen (GalNAcα1-O-Ser/Thr) to generate T antigen (Galβ1-3GalNAcα1-O-Ser/Thr). Then, the T antigen can be modified by various glycosyltransferases to form many types of extended structures, which are usually found in many healthy tissues. In the absence of functional COSMC, which is necessary for the formation of functional T-synthase, or in the absence of functional C1GALT1 triggered by unknown mechanisms, Tn antigen may be used as a substrate by ST6GalNAc-I, which transfers a Sia unit (from CMP-Sia) to the Tn antigen to form STn. GalNAc—N-acetylgalactosamine; Gal—Galactose; Sia—Sialic Acid.

Figure 2

Representation of the simplified structure of fibronectin from the N-terminal to the C-terminal portion, with cysteine residues and their binding domains consisting of type I (F-1), II (F-II) and III (F-III), and repeat domains comprising the fibrin, collagen, arginylglycylaspartic acid (RGD), FN, heparin and syndecan binding domains. Between F-I and F-III, there is a type III connecting segment (IIICS), which is the major binding site for the integrin α4β1, also known as VLA-4. Different peptide motifs may also be detected in the FN structure, such as EDB and EDA. During alternative splicing, more than 20 fibronectin isoforms can be generated, among which, some carry the IIICS domain (also known as the variable region) that contains the hexapeptide VTHPGY, which is glycosylated at the Thr residue by the action of GALNT6, generating the O-glycosylated fibronectin. O-glycosylated fibronectin is able to modulate both the EMT process and the acquisition/maintenance of the MDR phenotype in cancer cells.