Transfection of alpha(1,3)fucosyltransferase antisense sequences impairs the proliferative and tumorigenic ability of human colon carcinoma cells

Sialyl Lewis x and sialyl Lewis a are oncodevelopmental antigens involved i n the pathogenesis of colon adenacarcinoma. Biosynthesis of these glycans i s controlled by alpha(1,3/1,4)fucosyltransferases. We report the disruption of sialyl Lewis x/a biosynthesis and inhibition of colon carcinoma cell pr oliferation by stable transfection of antisense sequences directed at the h uman Lewis alpha(1,3/1,4)fucosyltransferase gene, FUT3, and the plasma alph a(1,3)fucosyltransferase ene, FUT6. COLO-205 cells expressed high levels of sialyl Lewis x/a, alpha(1,3)fucosyltransferase activity, and FUT3/6 transc ripts, but COLO-205-derived antisense transfectant cell lines AS5C and AS7A did not. Sense transfectant S6G expressed higher levels of fucosyltransfer ase than parental COLO-205. Cellular proliferation assays showed marked cor relative decreases in the growth of antisense lines and, conversely, increa sed growth of sense transfectants. Subcutaneous tumors created by injection of nude mice with antisense transfectant cell lines grew more slowly than those arising from control COLO-205 and sense transfectants. These results provide target validation for inhibition of carcinoma proliferation with an tisense sequences directed at human fucosyltransferases. (C) 2000 Wiley-Lis . Inc.