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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleToxicology

Up-Regulation of Extracellular Signal-Regulated Kinase 1/2-Dependent Thymidylate Synthase and Thymidine Phosphorylase Contributes to Cisplatin Resistance in Human Non–Small-Cell Lung Cancer Cells

Jen-Chung Ko, Min-Shao Tsai, Yu-Fan Chiu, Shao-Hsing Weng, Ya-Hsun Kuo and Yun-Wei Lin
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 184-194; DOI: https://doi.org/10.1124/jpet.111.179663
Jen-Chung Ko
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Min-Shao Tsai
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Yu-Fan Chiu
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Shao-Hsing Weng
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Ya-Hsun Kuo
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Yun-Wei Lin
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Abstract

Chemotherapy for advanced human non–small-cell lung cancer (NSCLC) includes platinum-containing compound such as cisplatin in combination with a second- or third-generation cytotoxic agent. 5-Fluorouracil (5-FU) belongs to antimetabolite chemotherapeutics, and its mechanism of cytotoxicity is involved in the inhibition of thymidylate synthase (TS). TS and thymidine phosphorylase (TP) are key enzymes of the pyrimidine salvage pathway. In this study, we have examined the molecular mechanism of TS and TP in regulating drug sensitivity to cisplatin in NSCLC cell lines. Cisplatin could increase the phosphorylation of mitogen-activated protein kinase kinase 1/2 (MKK1/2)-extracellular signal-regulated kinase 1/2 (ERK1/2) and the protein levels of TS and TP through enhancing the protein stability in A549 and H1975 cells. Blocking ERK1/2 activation by MKK1/2 inhibitor [U0126; 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene)] decreased TS and TP protein levels in both cell lines treated with cisplatin. Depletion of endogenous TS or TP expression by specific small interfering RNA transfection significantly increased cisplatin-induced cell death and growth inhibition. Combined treatment with 5-FU could decrease cisplatin-induced ERK1/2 activation and the induction of TS and TP, which subsequently resulted in synergistic cytotoxic effects. Enforced expression of constitutive active MKK1/2 vectors rescued the protein levels of phospho-ERK1/2, TS, and TP, and the cell viability that were decreased by cisplatin and 5-FU combination. In contrast, U0126 enhanced drug sensitivity to cisplatin and/or 5-FU in lung cancer cells. In conclusion, the up-regulation of ERK1/2-dependent TS and TP can protect human lung cancer cells from cisplatin-induced cytotoxicity.

Footnotes

  • This work was supported by the National Science Council of Taiwan [Grant NSC 99-2320-B-415-001-MY3]; and a research grant from Hsinchu General Hospital.

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

    doi:10.1124/jpet.111.179663.

  • ABBREVIATIONS:

    NSCLC
    non–small-cell lung cancer
    TS
    thymidylate synthase
    TP
    thymidine phosphorylase
    ALLN
    N-acetyl-Leu-Leu-norleucinal
    CI
    combination index
    MKK1/2
    mitogen-activated protein kinase kinase 1/2
    ERK1/2
    extracellular signal-regulated kinase 1/2
    siRNA
    small interfering RNA
    5-FU
    5-fluorouracil
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene)
    MG132
    N-(benzyloxycarbonyl)leucinylleucinylleucinal-Z-Leu-Leu-Leu-al
    DMSO
    dimethyl sulfoxide
    RT-PCR
    reverse transcription-polymerase chain reaction
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    MTS
    3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt
    MEF
    murine embryonic fibroblast.

  • Received January 19, 2011.
  • Accepted March 25, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleToxicology

Up-Regulation of Extracellular Signal-Regulated Kinase 1/2-Dependent Thymidylate Synthase and Thymidine Phosphorylase Contributes to Cisplatin Resistance in Human Non–Small-Cell Lung Cancer Cells

Jen-Chung Ko, Min-Shao Tsai, Yu-Fan Chiu, Shao-Hsing Weng, Ya-Hsun Kuo and Yun-Wei Lin
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 184-194; DOI: https://doi.org/10.1124/jpet.111.179663

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Research ArticleToxicology

Up-Regulation of Extracellular Signal-Regulated Kinase 1/2-Dependent Thymidylate Synthase and Thymidine Phosphorylase Contributes to Cisplatin Resistance in Human Non–Small-Cell Lung Cancer Cells

Jen-Chung Ko, Min-Shao Tsai, Yu-Fan Chiu, Shao-Hsing Weng, Ya-Hsun Kuo and Yun-Wei Lin
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 184-194; DOI: https://doi.org/10.1124/jpet.111.179663
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