A possible role of multidrug resistance-associated protein (MRP) in basic fibroblast growth factor secretion by AIDS-associated Kaposi's sarcoma cells: a survival molecule?

Abstract

Kaposi's sarcoma (KS) is considered a disorder of cytokines. Basic fibroblast growth factor (bFGF) is produced by AIDS-associated KS (AIDS-KS) cells and supports their growth in an autocrine and paracrine manner. bFGF lacks a signal sequence; therefore, its mechanism of secretion is unclear. In this study, we investigate the role of two important members of ATP-binding cassette transport proteins, the P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), in the secretion of bFGF from AIDS-KS cells. Expression of P-gp and MRP was examined at both the protein and the mRNA levels by flow cytometry and RT-PCR respectively. Intracellular and secreted bFGF was measured by ELISA. AIDS-KS cells expressed MRP at both the mRNA and the protein levels; however, no P-gp expression was detected at either the mRNA or the protein level. Probenecid, a putative inhibitor of MRP efflux function, in a concentration-dependent manner, inhibited bFGF secretion, with a concomitant increase in intracellular bFGF, demonstrating that probenecid blocks bFGF secretion without inhibiting its synthesis. In addition, probenecid induced apoptosis in AIDS-KS cells. AIDS-KS cells expressed fas, bcl-2, and bcl-xL genes but lacked fasL and bax gene expression. These data suggest that bFGF is secreted from AIDS-KS cells via a probencid-sensitive transporter, most likely in MRP. Furthermore, probenecid appears to induce apoptosis in AIDS-KS cells by depriving them of the growth promoting activity of bFGF. These data suggest that MRP may play a role as a survival molecule in AIDS-KS cells.