Role of SA-Le(a) and E-selectin in metastasis assessed with peptide antagonist.
E-selectin ligand Sialyl-Lewis a (SA-Le(a)) carbohydrate is expressed on many carcinomas. Peptide mimicking SA-Le(a) (DLWDWVVGKPAG) was previously selected from a recombinant library by screening with monoclonal antibody (MAb) NS19-9. In this study, the residues critical for interaction with the NS19-9 were mapped using peptide array generated by substitution of various amino acid residues. The replacement of Trp 5 with Phe resulted in a change of peptide's secondary structure and increased binding with MAb and E-selectin, suggesting improved carbohydrate mimicry. Colonization of tumor cells expressing SA-Le(a) was blocked by the peptide and was completely abolished in E-selectin knock out mice. The data suggest the critical role of carbohydrate antigens and E-selectin in metastasis and that peptides mimicking carbohydrate antigens can function as antagonists of this process.
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Insug
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The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Otvos
Laszlo
L
Kieber-Emmons
Thomas
T
Blaszczyk-Thurin
Magdalena
M
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000915:Antibody Affinity; D001667:Binding, Competitive; D018395:CA-19-9 Antigen; D002942:Circular Dichroism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005732:Gangliosides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D017353:Gene Deletion; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017433:Protein Structure, Secondary
D000911:Antibodies, Monoclonal; D018395:CA-19-9 Antigen; D019040:E-Selectin; D005732:Gangliosides; D008024:Ligands; D010455:Peptides; C064564:sialyl Le(a) ganglioside