Chitin or Chitin-Like Glycans as Targets for Late-Term Cancer Chemoprevention

Abstract

A consistent observation in studies of carcinogenesis is that some glycans are expressed differently in cancer cells than in normal cells. A well-known example is the aberrant b1-6 N-acetyl-D-glucosamine branching associated with metastasis and poor prognosis in many cancers. This commentary proposes that, although not found in normal mammalian cells, a chitin (b-1,4-linked N-acetyl-D-glucosamine) or a chitin-like polysaccharide (e.g., hyaluronan) may exist as a cancer-associated glycan, which can be targeted by the novel pyrimidine nucleotide derivative SP-1015 (designed as a chitin synthase inhibitor). Preliminary chemoprevention data of our group showed SP-1015 in the diet can inhibit benzo(a)pyreneinduced neoplasia in the forestomach of female A/J mice, and, of importance, this activity occurred at late stages in carcinogenesis. While no effect was seen in the murine lung, this may be due to the low bioavailability of the compound. A different route of administration (e.g. inhalation of an aerosol) may have potential to inhibit pulmonary carcinogenesis. We hypothesize that inhibitors of chitin or chitin-like glycan formation may be effective chemopreventive agents and suggest that further work is needed to study these novel targets for cancer prevention. Cancer Prev Res; 3(12); 1519-22. Ó2010 AACR. Glycans, Chitins, and CarcinogenesisA consistent observation in studies of carcinogenesis is that expression of glycans is different in cancer cells than in normal cells. Glycans-oligosaccharides or polysaccharides often attached to proteins or lipids-are found on the surfaces of all eukaryotic cells and in the extracellular matrix and some organelles. Glycans are formed in the process of glycosylation through the creation of glycosidic linkages, the bonds between carbohydrate units and other molecules. During glycosylation in the Golgi apparatus, glycotransferases (enzymes which form glycosidic linkages) and glycosidases (enzymes which cleave glycosidic linkages) often exhibit changed levels of expression in cancer cells compared with their normal cell counterparts. The resulting aberrant glycosylation leads to changes in the core glycan structure, such as altered branching and increased glycan size, and can lead to other changes in chemical composition associated with carcinogenesis. Thus, over-or underexpression of particular glycans, generally structurally modified from their normal-cell counterparts, is characteristic of cancer cells (reviewed in refs. 1-5).Perhaps the most-widely studied example of an aberrant structure associated with cancer cell surfaces is the occurrence of b1-6 branching on N-glycans between N-acetyl-D-glucosamine (GlcNAc) and mannose (Man). This branching is caused by the activity of the glycotransferase N-acetlyglucosaminyltransferase-V (GnT-V), which catalyzes the addition of GlcNAc to a particular Man residue on an asparagine-linked glycan, forming the branching structure GlcNAcb1-6-Mana1-6Manb1 ( Fig. 1; refs. 1-5). The additional branch provides an additional substrate for ...

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