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Originally published In Press as doi:10.1074/jbc.M203262200 on June 24, 2002

J. Biol. Chem., Vol. 277, Issue 41, 38998-39004, October 11, 2002
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Expression of MRP4 Confers Resistance to Ganciclovir and Compromises Bystander Cell Killing*

Masashi AdachiDagger §, Janardhan SampathDagger §, Lu-bin LanDagger , Daxi SunDagger , Philip Hargrove, Robin Flatley||, Ann TatumDagger , Mary Z. EdwardsDagger Dagger , Michele WezemanDagger Dagger , Larry Matherly||**, Richard Drake§§, and John SchuetzDagger ¶¶

From the Departments of Dagger  Pharmaceutical Sciences and  Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, the || Department of Pharmacology and the ** Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, the Dagger Dagger  Department of Biochemistry, University of Arkansas Center for Medical Sciences, Little Rock, Arkansas 72205, and the §§ Department of Biochemistry, Eastern Virginia Medical School, Norfolk, Virginia 23529

The multidrug resistance protein MRP4, a member of the ATP-binding cassette superfamily, confers resistance to purine-based antiretroviral agents. However, the antiviral agent ganciclovir (GCV) has not been shown to be a substrate of MRP4. GCV is important not only in antiviral therapy, but also in the selective killing of tumor cells modified to express herpes simplex virus thymidine kinase (HSV-TK). We therefore tested the effect of MRP4 on the cytotoxicity of GCV, on the ability of GCV to kill cells genetically modified to express HSV-TK, and on the bystander effect in which unmodified target cells are killed by GCV. Cells overexpressing MRP4 had markedly increased resistance to the cytotoxicity of GCV. Although, expression of recombinant HSV-TK increased the intracellular concentration of GCV nucleotide, cells were rescued by the cytoprotective effect of MRP4. In cells that overexpressed MRP4, intracellular accumulation of GCV metabolites was reduced, efflux of these metabolites was increased, and resistance to bystander killing was increased. Therefore, MRP4 can strongly reduce the susceptibility of HSV-TK-expressing cells to GCV, and its overexpression in adjacent cells protects them from bystander cell death. These findings indicate that a nucleotide transporter, such as MRP4, modulates the cellular response to GCV and thus may influence not only the efficacy of antiviral therapy, but also prodrug-based gene therapy, which is critically dependent upon bystander cell killing.

* This work was supported by National Institutes of Health Research Grants GM-60904, CA-63203, CA-23099, CA53535, P30 CA-21765, and CA83843 and by the American Lebanese Syrian Associated Charities (ALSAC).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY081219.

§ Both authors contributed equally to this work.

¶¶ To whom correspondence should be addressed: Dept. of Pharmaceutical Sciences, St. Jude Children's Research Hosp., 332 N. Lauderdale Ave., Memphis, TN 38105-2794. Tel.: 901-495-2174; Fax: 901-525-6869; E-mail: John.schuetz@stjude.org.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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