Increasing the α 2, 6 sialylation of glycoproteins may contribute to metastatic spread and therapeutic resistance in colorectal cancer

Abstract

Abnormal glycosylation due to dysregulated glycosyltransferases and glycosidases is a key phenomenon of many malignancies, including colorectal cancer (CRC). In particular, increased ST6 Gal I (β-galactoside α 2, 6 sialyltransferase) and subsequently elevated levels of cell-surface α 2, 6-linked sialic acids have been associated with metastasis and therapeutic failure in CRC. As many CRC patients experience metastasis to the liver or lung and fail to respond to curative therapies, intensive research efforts have sought to identify the molecular changes underlying CRC metastasis. ST6 Gal I has been shown to facilitate CRC metastasis, and we believe that additional investigations into the involvement of ST6 Gal I in CRC could facilitate the development of new diagnostic and therapeutic targets. This review summarizes how ST6 Gal I has been implicated in the altered expression of sialylated glycoproteins, which have been linked to CRC metastasis, radioresistance, and chemoresistance.

Keywords: Beta-D-galactoside alpha 2-6-sialyltransferase; Chemoresistance; Colorectal neoplasms; Neoplasm metastasis; Radioresistance.

Fig. 1

Types of N-glycans and the structure of N-acetyl neuraminic acid (Neu5Ac). (A) The N-glycans that may be added to proteins at asparagine (Asn) residues are of three general types: the oligomannose type, the complex type, and the hybrid type. Each N-glycan contains the common core: Man₃GlcNAc₂Asn. For symbolic representations of each monosaccharide and linkage, the International Union of Pure and Applied Chemistry short code, and symbolic nomenclature with geometric shapes used in Consortium for Functional Glycomics are shown. (B) Neu5Ac have nine carbons, a carboxylic acid residue at the 1 position, and a variety of linkages to the underlying sugar chain at the 2 position. Various substitutions at the 4, 7, 8, and 9 positions combine with the linkages to generate the wide diversity of sialic acids found in nature. Glc, glucose; Gal, galactose; GlcNAc, N-acetyl glucosamine; Man, mannose; Fuc, fucose.

Fig. 2

Schematic representation of the sialic acid metabolism pathway in eukaryotic cells. The synthesis, activation, conjugation, and breakdown of mammalian sialic acids (N-acetyl neuraminic acid, Neu5Ac) are shown. Sialic acid is taken in through the diet or synthesized in the cytosol. From there, it is transported into the nucleus, where cytidine monophosphate (CMP)-sialic acid is synthesized. In the Golgi apparatus, ST6 Gal I transfers the sialic acid from CMP-sialic acid to a glycoprotein. ST6 Gal I is cleaved by cathepsin-like proteases, and then released from the cell. The sialylated conjugates can be cleared by neuraminidases in lysosomes, the cytosol, the plasma membrane, and mitochondria. Gal, galactose; GlcNAc, N-acetyl glucosamine; Man, mannose; Neu, neuraminidase.

Fig. 3

ST6 galactose (Gal) I activity may be increased during the development of colorectal cancer (CRC). CRC arises through a series of well-characterized molecular and histopathologic changes that transform normal colonic epithelial cells into metastatic carcinoma cells. (A) Mutations in APC are required for tumor initiation, and the subsequent progression from adenoma to metastatic carcinoma is accompanied by genomic instability and sequential mutations in KRAS and p53, and other genes. (B) In vivo experimental results, splenic injections of CT26 cell treated with or without neuraminidase were used to examine hepatic metastasis of mouse CRC cells. (C) In vitro 3-dimensional (3D)-culture experiments show that ST6 Gal I-overexpressing SW480 human primary CRC cells are more invasive than control cells.

Fig. 4

Hypothetical pathway(s) for ST6 galactose (Gal) I-induced radioresistance and chemoresistance in colorectal cancer. EGFR, epidermal growth factor receptor; Neu5Ac, N-acetyl neuraminic acid; GlcNAc, N-acetyl glucosamine; Man, mannose.