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.
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.
Descheny
Leyla
L
Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Gainers
Madeliene E
ME
Walcheck
Bruce
B
Dimitroff
Charles J
CJ
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D020405:Dermis / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D017254:Leukemic Infiltration / Q000517:prevention & control*; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009844:Oligosaccharides / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D008562:Membrane Glycoproteins; D009844:Oligosaccharides; C084882:P-selectin ligand protein; D017468:Receptors, Fibroblast Growth Factor; D016201:Receptors, Lymphocyte Homing; D012795:Sialoglycoproteins; D000080506:Sialyl Lewis X Antigen; C086711:cysteine-rich fibroblast growth factor receptor; C089178:2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoroglucopyranose; D000117:Acetylglucosamine