Enhanced expression of human ABC-transporter tap is associated with cellular resistance to mitoxantrone

Multidrug resistance (MDR) phenotypes have been associated with the overexp ression of various members of the superfamily of ATP binding cassette (ABC) transporters. Here we demonstrate that a member of the ABC-transporter fam ily, the heterodimer transporter associated with antigen processing' (TAP), physiologically involved in major histocompatibility complex class I-restr icted antigen presentation, is significantly overexpressed in the human gas tric carcinoma cell line EPG85-257RNOV exhibiting a mitoxantrone-resistant phenotype. This tumor cell line shows an atypical MDR phenotype in the abse nce of 'P-glycoprotein' or 'MDR-associated protein' overexpression but with an enforced 'breast cancer resistance protein' expression level. Transfect ion of both TAP subunits encoding cDNA molecules, TAP1 and TAP2, into the d rug-sensitive parental gastric carcinoma cell line EPG85-257P conferred a 3 .3-fold resistance to mitoxantrone but not to alternative anti-neoplastic a gents. Furthermore, cell clones transfected with both, but not singularly e xpressed TAN or TAP2, reduced cellular mitoxantrone accumulation. Taken tog ether, the data suggest that the heterodimeric TAP complex possesses charac teristics of a xenobiotic transporter and that the TAP dimer contributes to the atypical MDR phenotype of human cancer cells. (C) 2001 Published by El sevier Science B.V. on behalf of the Federation of European Biochemical Soc ieties.