Glycan changes, in addition to being traditional mediators of protein quality control, cell signaling, and metabolism, are intimately linked to the progression of cancer and can potentially act as novel therapeutic and diagnostic targets. Despite advances in our understanding that glycosylation plays a key role in protein folding, maturation, and function, there is only limited understanding of the interconnected nature of glycan alterations to endoplasmic reticulum stress, the unfolded protein response, and the development of cancer. This review aims to highlight the interdependence of these pathways and the way they feed into each other to maintain protein quality control, regulate key survival mechanisms, and promote cell viability.
Sialidases are enzymes that catalyze the removal of sialic acids from glycoproteins and glycolipids. Previously, we have studied the effect of sialidase inhibition as a modulator of sialylation-related mechanisms of invasion and found that it induces aggressiveness in canine mammary tumors (CMTs). In this study, we aimed to assess the expression of glycoprotein-acting sialidases, Neu1, Neu2, and Neu4, in the complex multistage process of cancer metastasis. Thus, we examined their expression in a series of spontaneous malignant CMTs, CMT cell lines, and nude mice xenografts. All malignant CMT lesions expressed mammalian sialidases, although overall decreased when compared to normal adjacent mammary tissues. This difference was statistically significant regarding Neu4. In accordance, CMA07 adenoma cell line expressed higher levels of sialidase protein expression when compared with the CMT-U27 carcinoma cell line. Finally, with few tumor subpopulation exceptions, Neu1 and Neu4 expression was also overall low in primary and metastatic CMT xenografts. Thus, overall loss of sialidases seems to be an important feature for CMT progression and invasion.
Galectins are a family of β-galactoside-binding proteins that share a consensus sequence in the carbohydrate recognition domain (CRD). Galectin-3 is the most widely studied family member and can be found in the cellular cytoplasm and nucleus, as well as extracellularly in various tissues. The 30-kDa molecule contains an N-terminal proline-rich domain that is important for its oligomerization and a C-terminal CRD for carbohydrate-binding activity. Many studies have shown that galectin-3 may regulate inflammation through a variety of mechanisms. Endogenous galectin-3 has been shown to be involved in the pathogenesis of various diseases, such as fibrosis in the lung, liver, and heart, diabetes mellitus, coronary artery disease, and allergic diseases. In this review, we briefly discuss the pro- or anti-inflammatory roles, as well as potential clinical implications of galectin-3 in these disorders.
Galectins are a family of proteins that contain a canonical carbohydrate-recognition domain (CRD) with affinity for beta-galactosides. Within this family, an unique member, the chimeric, galectin-3, may be found in the cytoplasm and nucleus, and on the cell surface, besides being released into the extracellular space. Galectin-3 interactions with certain glycans and extracellular matrix (ECM) proteins have been described to promote and/or antagonize tumor cell apoptosis, to induce endothelial cell proliferation and angiogenesis, and to promote tumor cell adhesion and invasion, thus both potentially facilitating and hindering metastasis. Moreover, although galectin-3 is expressed in several types of malignancies and its expression has been correlated with transformation and metastasis-related events, its downregulation has also been associated with malignancy and tumor progression. These apparently conflicting data demonstrate that the role of galectin-3 in metastasis remains to be fully understood. Of course in nature, different cancer progression phenomena are simultaneously occurring in the many instances, where the patient has primary tumor and blood-borne and distant metastatic cells. This makes it all the more interesting to overview the role of galectins in cancer metastasis, especially galectin-3, since these and their related molecules are more than probable disease marker candidates and/or therapeutic targets.
Resveratrol was glucosylated to its 3- and 4'-β-glucosides by the glucosyltransferase PaGT3 from Phytolacca americana expressed in Bacillus subtilis. PaGT3 glucosylated pterostilbene to its 4'-β-glucoside. Piceatannol was converted into its 4'-β-glucoside by PaGT3. Resveratrol 3-β-glucoside showed the inhibitory action of adhesion, migration, and invasion of KB cells. The resveratrol 3-β-glucoside would act as a chemopreventive agent against KB cells. Piceatannol 4'-β-glucoside showed the strongest inhibitory activity among the glycosides toward histamine release from rat peritoneal mast cells. The 4'-β-glucoside of piceatannol would be a potential therapeutic agent for allergic disease. Pterostilbene 4'-β-glucoside showed high phosphodiesterase (PDE) inhibitory activity. The 4'-β-glucoside of pterostilbene could be a potential chemopreventive agent for Alzheimer’s disease.
