Selective loss of nucleoside carrier expression in rat hepatocarcinomas

Authors

  • Yvonne Dragan,

    1. McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine, University of Wisconsin, Madison, WI
    Current affiliation:
    1. Y.D.'s present address is Ohio State University, 1148 James CHRI, 300 W. 10th Ave., Columbus, OH 43210.
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  • Raquel Valdés,

    1. Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain
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  • Mireia Gomez-Angelats,

    1. McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine, University of Wisconsin, Madison, WI
    Current affiliation:
    1. M.G.-A.'s present address is NIEHS, National Institutes of Health, POB 12133, 111 Alexander Drive, Research Triangle Park, NC 27709.
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  • Antonio Felipe,

    1. Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain
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  • F. Javier Casado,

    1. Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain
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  • Henry Pitot,

    1. McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine, University of Wisconsin, Madison, WI
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  • Marçal Pastor-Anglada Ph.D.

    Corresponding author
    1. Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain
    • Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain. fax: (34) 93-4021559.
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Abstract

Evidence that hepatoma cell lines show differential expression of concentrative nucleoside transporters (CNT1 and CNT2) prompted us to study the transporter proteins in 2 models of hepatocarcinogenesis, the chemically induced Solt and Farber model and the albumin-SV40 large T antigen (Alb-SV40) transgenic rat. CNT1 expression was lower in tumor biopsy specimens from Alb-SV40 rat livers than in normal tissue. Immunocytochemistry revealed that the CNT1 protein was indeed absent in the tumor lesions. CNT1 was also absent in a cell line, L25, derived from the Alb-SV40 transgenic rat liver tumors, whereas another cell line, L37, derived from the normal-appearing parenchyma, retained the expression of both carrier isoforms. The protein expression correlated with the nucleoside transport properties of these cell lines. Moreover, although CNT2 expression was highly dependent on the growth characteristics of the 2 cell lines, as was CNT1 (albeit to a lower extent) in L37 cells, it was not expressed in L25 cells at any stage of cell growth. In contrast to the transgenic model of hepatocarcinogenesis, in the chemically induced tumors the expression of CNT2 was lower, although still detectable. In summary, these data indicate that hepatocarcinogenesis leads to a selective loss or diminished expression of nucleoside carrier isoforms, a feature that may be relevant to our understanding of the molecular basis of the bioavailability of those drugs that are nucleoside derivatives and may be substrates of these carriers. The transport properties and isoform-expression profile of the L25 and L37 cell lines make them suitable hepatocyte culture models with which to study nucleoside transport processes and drug sensitivity.

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