OVEREXPRESSION OF THE ABC TRANSPORTER TAP IN MULTIDRUG-RESISTANT HUMAN CANCER CELL-LINES

Multidrug resistance (MDR) to anti-cancer drugs has been associated wi th the overexpression of P-glycoprotein (P-gp) and the multidrug resis tance-associated protein (MRP), both being members of the ATP-binding cassette (ABC) superfamily of transporters. We investigated whether in addition to P-gp and MRP, another ABC transporter, the transporter as sociated with antigen processing (TAP), is associated with MDR. TAP pl ays a major role in MHC class I-restricted antigen presentation by med iating peptide translocation over the endoplasmic reticulum membrane. TAP1 and P-gp share a significant degree of homology among their trans membrane domains, which are thought to be the primary determinants of substrate specificity, and both can apparently mediate the translocati on of peptides. Using immunocytochemistry and Western blot, TAP was ov erexpressed in parallel with MHC class I in several MDR human cancer c ell lines. TAP was overexpressed more frequently in MRP-positive MDR c ell lines (three our of three) than in P-gp positive MDR cells (two ou t of five). Reversal of resistance resulted in a decrease in TAP level s. Transfection of the TAP genes into TAP-deficient lymphoblastoid T2 cells conferred mild resistance to etoposide, vincristine and doxorubi cin (2- to 2.5-fold). Furthermore, etoposide and vincristine inhibited TAP-dependent peptide translocation to the endoplasmic reticulum. Col lectively, our results suggest that TAP may modestly contribute to the MDR phenotype, in particular in MRP- overexpressing MDR cells. Furthe r insight into the role of TAP in MDR will require the study of other transfectants, as well as the investigation of TAP expression in F-gp and MRP-negative MDR cancer cell lines.