Ameliorating skin-homing receptors on malignant T cells with a fluorosugar analog of N-acetylglucosamine: P-selectin ligand is a more sensitive target than E-selectin ligand.

Abstract

Expression of E- and P-selectin ligands is required for T cell entry into skin. Sialyl Lewis X moieties are critical for ligand activity and are elevated on malignant skin-homing T cells. We hypothesize that these glycosylations are selectable targets for treating the dermal tropism associated with cutaneous lymphomas. In this study, we analyzed the efficacy of a novel 4-fluorinated analog of N-acetylglucosamine (GlcNAc) on E- and P-selectin ligands expressed by malignant skin-homing T cells. We also examined the specificity of 4-F-GlcNAc (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose) action by contrasting the effects on sialyl Lewis X expression displayed by P-selectin glycoprotein ligand-1 (PSGL-1) with sialylated O-glycans expressed by CD43. Using parallel-plate flow analysis, we found that 4-F-GlcNAc elicited 5-fold more potent inhibition on P-selectin ligand activity than on E-selectin ligand activity. To determine whether glycosylations conferring E- and P-selectin ligand activities were inhibited, we analyzed the expression of sialyl Lewis X and sialyl-fucosylated core 2 O-glycan (CHO-131 antigen), respectively. We found that 4-F-GlcNAc treatment resulted in dose-dependent ablation of sialyl Lewis X and CHO-131 antigen expression on PSGL-1, whereas sialylated O-glycans on CD43 were minimally affected. These results indicate that 4-F-GlcNAc treatment can selectively downregulate the P-selectin ligand activity and potentially prevent dermal dissemination of cutaneous lymphomas.

• Authors: Leyla Descheny, Madeliene E Gainers, Bruce Walcheck, Charles J Dimitroff
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 126 Issue 9 Pg. 2065-73 (Sep 2006) ISSN: 0022-202X [Print] United States
• PMID: 16691194 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Membrane Glycoproteins
• Oligosaccharides
• P-selectin ligand protein
• Receptors, Fibroblast Growth Factor
• Receptors, Lymphocyte Homing
• Sialoglycoproteins
• Sialyl Lewis X Antigen
• cysteine-rich fibroblast growth factor receptor
• 2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoroglucopyranose
• Acetylglucosamine

Topics

• Acetylglucosamine (analogs & derivatives, metabolism, pharmacology)
• Cell Line, Tumor
• Dermis (immunology, pathology)
• Down-Regulation (drug effects, immunology)
• Flow Cytometry
• Humans
• In Vitro Techniques
• Leukemic Infiltration (prevention & control)
• Lymphoma, T-Cell (drug therapy, pathology)
• Membrane Glycoproteins (metabolism)
• Oligosaccharides (metabolism)
• Receptors, Fibroblast Growth Factor (metabolism)
• Receptors, Lymphocyte Homing (metabolism)
• Sialoglycoproteins (metabolism)
• Sialyl Lewis X Antigen
• T-Lymphocytes (cytology, drug effects, metabolism)