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High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase

  • Authors:
    • Wei-Ting Kuo
    • Dom-Gene Tu
    • Ling-Yen Chiu
    • Gwo-Tarng Sheu
    • Ming-Fang Wu
  • View Affiliations / Copyright

    Affiliations: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan, R.O.C., Department of Nuclear Medicine, Ditmanson Medical Foundation, Chia‑Yi Christian Hospital, Chiayi City 60002, Taiwan, R.O.C., Institute of Medicine, Chung Shan Medical University, Taichung City 402, Taiwan, R.O.C., School of Medicine, Chung Shan Medical University, Taichung City 402, Taiwan, R.O.C.
    Copyright: © Kuo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2787-2795
    |
    Published online on: September 7, 2017
       https://doi.org/10.3892/or.2017.5951
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Abstract

The chemoresistance of non-small cell lung cancer (NSCLC) that occurs in docetaxel (DOC) chemotherapy substantially decreases the survival of patients. To overcome DOC-induced chemoresistance, we established DOC-selected A549 lung cancer sublines (A549/D16 and A549/D32) and revealed that both sublines were cross-resistant to vincristine (VCR) and doxorubicin (DXR). Notably, both sublines were more sensitive to pemetrexed (PEM) than parental cells according to MTT and clonogenic assays. The expression levels of thymidylate synthase (TS) and γ-glutamyl hydrolase (GGH) were downregulated in DOC-resistant sublines. When exogenous TS was overexpressed in A549/D16 cells, PEM sensitivity was significantly decreased, however it was not decreased by overexpression of exogenous GGH. PEM treatment induced more apoptotic sub-G1 cells in both DOC-resistant sublines and in the in vivo PEM sensitivities of A549/D16 cells. These findings were further confirmed by a xenografted tumor model. To unmask the mediator of TS downregulation, we investigated human lung cancer cell lines that have various TP53 statuses using DOC treatment. The level of TS protein was significantly decreased in wild-type TP53-containing cells with DOC treatment; TS expression levels were not affected in mutant-TP53 and TP53‑null cells under the same conditions. Furthermore, when the expression of TP53 was inhibited in A549 cells, the expression level of TS was increased. Our data indicated that DOC activated wild-type TP53 and suppressed TS expression under continuous DOC exposure. Therefore, the expression of TS remained at low levels in DOC-resistant A549 cancer cells. Our data revealed that for lung cancer with DOC resistance and wild‑type TP53 status, the administration of PEM as a second-line agent to overcome DOC-resistance may benefit patients.
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Copy and paste a formatted citation
Spandidos Publications style
Kuo W, Tu D, Chiu L, Sheu G and Wu M: High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase. Oncol Rep 38: 2787-2795, 2017.
APA
Kuo, W., Tu, D., Chiu, L., Sheu, G., & Wu, M. (2017). High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase. Oncology Reports, 38, 2787-2795. https://doi.org/10.3892/or.2017.5951
MLA
Kuo, W., Tu, D., Chiu, L., Sheu, G., Wu, M."High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase". Oncology Reports 38.5 (2017): 2787-2795.
Chicago
Kuo, W., Tu, D., Chiu, L., Sheu, G., Wu, M."High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase". Oncology Reports 38, no. 5 (2017): 2787-2795. https://doi.org/10.3892/or.2017.5951
Copy and paste a formatted citation
x
Spandidos Publications style
Kuo W, Tu D, Chiu L, Sheu G and Wu M: High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase. Oncol Rep 38: 2787-2795, 2017.
APA
Kuo, W., Tu, D., Chiu, L., Sheu, G., & Wu, M. (2017). High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase. Oncology Reports, 38, 2787-2795. https://doi.org/10.3892/or.2017.5951
MLA
Kuo, W., Tu, D., Chiu, L., Sheu, G., Wu, M."High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase". Oncology Reports 38.5 (2017): 2787-2795.
Chicago
Kuo, W., Tu, D., Chiu, L., Sheu, G., Wu, M."High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase". Oncology Reports 38, no. 5 (2017): 2787-2795. https://doi.org/10.3892/or.2017.5951
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