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

Oncogene volume 19, pages 395–402 (2000)Cite this article

Abstract

A major obstacle in the systemic treatment of advanced malignant melanoma is its intrinsic resistance to conventionally used chemotherapeutic agents. In order to investigate the mechanisms of this intrinsic resistance, we have previously utilized retroviral insertional mutagenesis on an early-stage, drug sensitive human melanoma cell line (WM35) to establish mutated cell lines that exhibited increased resistance to cis-diamminedichloroplatinum(II) (CDDP). Here, we demonstrate that this increased resistance to CDDP is mediated by the over-expression of tyrosinase-related protein-2 (TYRP2), an enzyme 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 cell lines positively correlated with their levels of resistance to CDDP. Furthermore, enforced expression of TYRP2 in WM35 cells by transfection elevated their resistance to CDDP. The increased CDDP resistance in the virally-derived clones and TYRP2 transfectants was accompanied by a reduction in CDDP-induced apoptosis. Interestingly, the virally-derived CDDP-resistant clones also showed cross resistance to carboplatin and methotrexate, but not taxol, suggesting that TYRP2 over-expression may confer resistance specifically to DNA damaging agents. Overall, these results demonstrate a novel mechanism 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 mechanism of drug resistance. In summary, these findings suggest a significant role for TYRP2 in the intrinsic drug resistance phenotype of human melanoma cells and may have important implications in the development of chemosensitization strategies for the clinical management of this disease.

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Acknowledgements

The authors would like to thank Dr Rick Sturm (University of Queensland, Australia) for generously providing TYRP2 cDNA, Dr Vincent J Hearing (National Cancer Institute, Bethesda, MD, USA) for the αPEP8 TYRP2 polyclonal antibody and Dr Meenhard Herlyn (Wistar Institute, Philadelphia, PA, USA) for kindly providing the human melanoma cell lines. We also thank Dr Janusz Rak for helpful discussions and comments on the manuscript. This work was supported by grants from the Medical Research Council of Canada and the National Cancer Institute of Canada to Y Ben-David and the National Institutes of Health, USA (CA-41233) to RS Kerbel. BJ Pak is a recipient of the Sunnybrook Trust for Medical Research postdoctoral fellowship.

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Author notes

  1. Monika Kapoor

    Present address: M Negri Institute for Pharmacological Research, Bergamo, Italy

  2. Shi-Jiang Lu

    Present address: Department of Pediatrics-505 CUMINGS, Michael Reese Hospital and Medical Center, 2929 South Ellis Avenue, Chicago, 60616, IL, USA

Authors and Affiliations

  1. Division of Cancer Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada

    Wendy Chu, Brian J Pak, Maria Rosa Bani, Monika Kapoor, Shi-Jiang Lu, Ami Tamir, Robert S Kerbel & Yaacov Ben-David

  2. Department of Medical Biophysics, University of Toronto, Ontario, Canada

    Robert S Kerbel & Yaacov Ben-David

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  1. Wendy Chu
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Chu, W., Pak, B., Bani, M. et al. Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis-diamminedichloroplatinum(II): therapeutic implications. Oncogene 19, 395–402 (2000). https://doi.org/10.1038/sj.onc.1203315

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