Tyrosinase-related protein 2 as a mediator of melanoma specific resistanceto cis-diamminedichloroplatinum(II): therapeutic implications

A major obstacle in the systemic treatment of advanced malignant melanoma i s its intrinsic resistance to conventionally used chemotherapeutic agents. In order to investigate the mechanisms of this intrinsic resistance, we hav e previously utilized retroviral insertional mutagenesis on an early-stage, drug sensitive human melanoma cell line (WM35) to establish mutated cell l ines that exhibited increased resistance to cis-diamminedichloroplatinum(II ) (CDDP), Here, we demonstrate that this increased resistance to CDDP is me diated by the over-expression of tyrosinase-related protein-2 (TYRP2), an e nzyme that normally functions in the biosynthesis of the pigment, melanin. Northern and Western blot analyses revealed that the expression of TYRP2 in the virally-derived cell lines as well as in a panel of human melanoma cel l lines positively correlated with their levels of resistance to CDDP, Furt hermore, enforced expression of TYRP2 in WM35 cells by transfection elevate d their resistance to CDDP, The increased CDDP resistance in the virally-de rived clones and TYRP2 transfectants was accompanied by a reduction in CDDP -induced apoptosis, Interestingly, the virally-derived CDDP-resistant clone s also showed cross resistance to carboplatin and methotrexate, but not tax ol, suggesting that TYRP2 over-expression may confer resistance specificall y to DNA damaging agents, Overall, these results demonstrate a novel mechan ism of drug resistance in human melanoma cells that is mediated by the over -expression of TYRP2, Since TYRP2 is expressed only in cells of melanocytic lineage, this may represent the first report of a lineage-specific mechani sm of drug resistance, In summary, these findings suggest a significant rol e for TYRP2 in the intrinsic drug resistance phenotype of human melanoma ce lls and may have important implications in the development of chemosensitiz ation strategies for the clinical management of this disease.