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(American Journal of Pathology. 2004;164:371-383.)
© 2004 American Society for Investigative Pathology

Short Communication

Transgene Expression of {alpha}(1,2)-Fucosyltransferase-I (FUT1) in Tumor Cells Selectively Inhibits Sialyl-Lewis x Expression and Binding to E-Selectin without Affecting Synthesis of Sialyl-Lewis a or Binding to P-Selectin

Sylvie Mathieu*, Maëlle Prorok*, Anne-Marie Benoliel{dagger}, Rathviro Uch{ddagger}, Claire Langlet*, Pierre Bongrand{dagger}, René Gerolami{ddagger} and Assou El-Battari*

From the Faculté de Médecine,* INSERM U-559/UEA-3289, Marseille; the Laboratoire d’Immunologie,{dagger} INSERM U-387, Hôpital de Sainte-Marguerite, Marseille; and the Etablissement Français du Sang Alpes-Méditerranée,{ddagger} Marseille, France

During inflammation, E- and P-selectins appear on activated endothelial cells to interact with leukocytes through sialyl-Lewis x and sialyl-Lewis a antigens (sLex/a). These selectins can also interact with tumor cells in a sialyl-Lewis-dependent manner and for this reason, they are thought to play a key role in metastasis. Diverting the biosynthesis of sialyl-Lewis antigens toward nonadhesive structures is an attractive gene therapy for preventing the hematogenous metastatic spread of cancers. We have previously shown that transfection of {alpha}(1,2)-fucosyltransferase-I (FUT1) in Chinese hamster ovary (CHO) cells had a slight effect on the overall sialylation while the synthesis of sLEx was dramatically prevented. We herein delivered the gene of FUT1 by a human immunodeficiency virus-derived lentiviral vector to three human cancer cell lines including pancreatic (BxPC3), hepatic (HepG2), and colonic (HT-29) cancer cells. We found that on FUT1 transduction, all cells exhibited a dramatic decrease in sLex synthesis with a concomitant increase in Ley and Leb expression, without any detectable effect on the level of cell surface sLea antigens. In parallel, FUT1-transduced HT-29 and HepG2 cells, but not BxPC3 cells, failed to interact with E-selectin as assessed by E-selectin-binding assay or dynamic adhesion to activated endothelial cells. We show also that transduced FUT1 efficiently fucosylates the P-selectin ligand PSGL-1 without altering P-selectin binding. These results have important implications for understanding cell-specific reactions underlying the synthesis of selectin ligands in cancer cells and may provide a basis for the development of anti-metastatic gene therapy.




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