Molecular mechanism for cancer-associated induction of sialyl Lewis X and sialyl Lewis A expression - The Warburg effect revisited

Cell adhesion mediated by selectins and their carbohydrate ligands, sialyl Lewis X and sialyl Lewis A, figures heavily in cancer metastasis. Expression of these carbohydrate determinants is markedly enhanced in cancer cells, but the molecular mechanism that leads to cancer-associated expression of sialyl Lewis X/A has not been well understood. Results of recent studies indicated involvement of two principal mechanisms in the accelerated expression of sialyl Lewis X/A in cancers; 'incomplete synthesis' and 'neosynthesis.' As to 'incomplete synthesis,' we have recently found further modified forms of sialyl Lewis X and sialyl Lewis A in non-malignant colonic epithelium, which have additional 6-sulfation or 2 --> 6 sialylation. The impairment of GlcNAc 6-sulfation and 2 --> 6 sialylation upon malignant transformation leads to accumulation of sialyl Lewis X/A in colon cancer cells. Epigenetic changes such as DNA methylation and/or histone deacetylation are suggested to lie behind such incomplete synthesis. As to the mechanism called 'neosynthesis,' recent studies have indicated that cancer-associated alterations in the sugar transportation and intermediate carbohydrate metabolism play important roles. Cancer cells are known to exhibit a metabolic shift from oxidative to elevated anaerobic glycolysis (Warburg effect), which is correlated with the increased gene expression of sugar transporters and glycolytic enzymes induced by common cancer-specific genetic alterations. The increased sialyl Lewis X/A expression in cancer is a link in the chains of these events because our recent results indicated that these events accompany transcriptional induction of a set of genes closely related to its expression.