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    標題: High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase
    作者: Kuo, Wei-Ting
    Tu, Dom-Gene
    Chiu, Ling-Yen
    Sheu, Gwo-Tarng
    Wu, Ming-Fang
    貢獻者: Natl Yang Ming Univ, Inst Clin Med
    Chia Yi Christian Hosp, Dept Surg
    Chia Yi Christian Hosp,Ditmanson Med Fdn, Dept Nucl Med
    Chia Nan Univ Pharm & Sci, Dept Food Sci & Technol
    Chang Jung Christian Univ, Coll Hlth Sci
    Chung Shan Med Univ Hosp, Inst Med
    Chung Shan Med Univ Hosp, Sch Med
    Chung Shan Med Univ Hosp, Div Med Oncol
    Chung Shan Med Univ Hosp, Div Chest Med
    關鍵字: docetaxel
    pemetrexed
    thymidylate synthase
    TP53
    chemoresistance
    日期: 2017-11
    上傳時間: 2018-11-30 15:55:04 (UTC+8)
    出版者: Spandidos Publ Ltd
    摘要: 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 gamma-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.
    關聯: Oncology Reports, v.38, n.5, pp.2787-2795
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