Enhanced GM3 expression, associated with decreased invasiveness, is induced by brefeldin A in bladder cancer cells

We reported previously that non-invasive bladder cancer expresses high leve l of GM3 ganglioside, whereas invasive tumors have low levels. Since glycos phingolipid synthesis in Golgi is modified greatly by a macrocyclic lactone isolated from fungi, brefeldin A (BFA), we studied effects of BFA on expre ssion of glycosphingolipids and on invasiveness of bladder cancer cell line s. Only GM3 synthesis in invasive tumors was greatly enhanced upon treatmen t with BFA; synthesis of other glycosphingolipids with lacto-series type 2 or globo-series structure in both invasive and noninvasive tumors was not c hanged. Invasiveness of bladder cancer cells was greatly decreased in assoc iation with the great increase of GM3 synthesis induced by BFA treatment. L evel of sialyl-Le(2), expressed in invasive cell line YTS1, which provides the adhesive property of the cells to E-selectin, was unchanged upon BFA tr eatment. All the bladder cancer cell lines, regardless of invasiveness, hig hly express tetraspanin CD9. GM3 has been implicated as a co-factor of CD9 in control of tumor cell motility. Down-regulation of CD9 is associated wit h metastatic properties of tumor cells and survival of patients with coloni c cancer. Therefore, enhanced synthesis of GM3 induced by BFA, causing decr ease of invasiveness in bladder cancer, is ascribable to the capability of GM3 to interconnect integrin with CD9, in analogy to colonic cancer and per haps many other types of cancer.