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Molecular Pharmacology

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Research ArticleArticle

Mitochondrial Expression of the Drosophila melanogaster Multisubstrate Deoxyribonucleoside Kinase

Nicola Solaroli, Xinyu Zheng, Magnus Johansson, Jan Balzarini and Anna Karlsson
Molecular Pharmacology December 2007, 72 (6) 1593-1598; DOI: https://doi.org/10.1124/mol.107.037051
Nicola Solaroli
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Xinyu Zheng
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Magnus Johansson
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Jan Balzarini
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Anna Karlsson
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Abstract

The multisubstrate deoxyribonucleoside kinase from Drosophila melanogaster deoxyribonucleoside kinase (Dm-dNK) is studied as a candidate suicide gene for applications in combined gene/chemotherapy of cancer. We have created an engineered Dm-dNK nucleoside kinase that is targeted to the mitochondrial matrix. The enzyme was expressed in a thymidine kinase 1-deficient osteosarcoma cell line, and the sensitivity of the cells to cytotoxic nucleoside analogs was determined when the enzyme was targeted to either the nucleus or the mitochondrial matrix. Although the total deoxythymidine (dThd) phosphorylation activity was similar in cells expressing Dm-dNK in the nucleus or in the mitochondria, the cells expressing the enzyme in the mitochondria showed higher sensitivity to the antiproliferative activity of several pyrimidine nucleoside analogs, such as (E)-5-(2-bromovinyl)-2′-deoxyuridine, 5-bromo-2′-deoxyuridine, and 5-fluoro-2′-deoxyuridine. Labeling studies using [3H]dThd showed that the cells expressing the mitochondrial enzyme had an increased incorporation of [3H]dThd into DNA, shown to be due to a higher [3H]dTTP specific activity of the total dTTP pool in the cells in which Dm-dNK was targeted to the mitochondria. The difference in the specific activity of the dTTP pool is a result of different contributions of the de novo and the salvage pathways for the dTTP synthesis in transduced cells. In summary, these findings suggest that mitochondrial targeting of Dm-dNK facilitates nucleoside and nucleoside analog phosphorylation and could be used as a strategy to enhance the efficacy of nucleoside analog phosphorylation and concomitantly their cytostatic potential.

Footnotes

  • This work was supported by grants from the Swedish Medical Research Council, the Swedish Cancer Foundation, and the European Commission.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.037051.

  • ABBREVIATIONS:Dm-dNK, Drosophila melanogaster deoxyribonucleoside kinase; TK1, thymidine kinase 1; dThd, deoxythymidine; dUrd, deoxyuridine; TK2, thymidine kinase 2; OST TK-, osteosarcoma thymidine kinase 1-deficient cells; FACS, fluorescence-activated cell sorting; GFP, green fluorescent protein; PBS, phosphate-buffered saline; AraT, 9-β-d-arabinofuranosylthymine; BVDU, (E)-5-(2-bromovinyl)-2′-deoxyuridine; 5-FdUrd, 5-fluoro-2′-deoxyuridine; wt, wild type.

    • Received April 12, 2007.
    • Accepted September 12, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (6)
Molecular Pharmacology
Vol. 72, Issue 6
1 Dec 2007
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Research ArticleArticle

Mitochondrial Expression of the Drosophila melanogaster Multisubstrate Deoxyribonucleoside Kinase

Nicola Solaroli, Xinyu Zheng, Magnus Johansson, Jan Balzarini and Anna Karlsson
Molecular Pharmacology December 1, 2007, 72 (6) 1593-1598; DOI: https://doi.org/10.1124/mol.107.037051

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Research ArticleArticle

Mitochondrial Expression of the Drosophila melanogaster Multisubstrate Deoxyribonucleoside Kinase

Nicola Solaroli, Xinyu Zheng, Magnus Johansson, Jan Balzarini and Anna Karlsson
Molecular Pharmacology December 1, 2007, 72 (6) 1593-1598; DOI: https://doi.org/10.1124/mol.107.037051
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