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Methotrexate induces apoptosis through p53/p21-dependent pathway and increases E-cadherin expression through downregulation of HDAC/EZH2

  1. Author:
    Huang, W. Y.
    Yang, P. M.
    Chang, Y. F.
    Marquez, V. E.
    Chen, C. C.

  2. Author Address

    [Huang, Wen-Yu; Yang, Pei-Ming; Chang, Yu-Fan; Chen, Ching-Chow] Natl Taiwan Univ, Coll Med, Dept Pharmacol, Taipei 10018, Taiwan. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA.;Chen, CC, Natl Taiwan Univ, Coll Med, Dept Pharmacol, 1,Jen Ai Rd,Sect 1, Taipei 10018, Taiwan.;chingchowchen@ntu.edu.tw
    1. Year: 2011
    2. Date: Feb
  2. Journal: Biochemical Pharmacology
    1. 81
    2. 4
    3. Pages: 510-517
  4. Type of Article: Article
  5. ISSN: 0006-2952
  1. Abstract:

    Methotrexate (MTX) is a dihydrofolate reductase (DHFR) inhibitor widely used as an anticancer drug in different kinds of human cancers. Here we investigated the anti-tumor mechanism of MTX against non-small cell lung cancer (NSCLC) A549 cells. MTX not only inhibited in vitro cell growth via induction of apoptosis, but also inhibited tumor formation in animal xenograft model. RNase protection assay (RPA) and RT-PCR demonstrated its induction of p53 target genes including DR5, p21, Puma and Noxa. Moreover, MTX promoted p53 phosphorylation at Ser15 and acetylaion at Lys373/382, which increase its stability and expression. The apoptosis and inhibition of cell viability induced by MIX were dependent on p53 and, partially, on p21. In addition, MIX also increased E-cadherin expression through inhibition of histone deacetylase (HDAC) activity and downregulation of polycomb group protein enhancer of zeste homologue 2 (EZH2). Therefore, the anticancer mechanism of MIX acts through initiation of p53-dependent apoptosis and restoration of E-cadherin expression by downregulation of HDAC/EZH2. (c) 2010 Elsevier Inc. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.bcp.2010.11.014
  3. View record in Web of Science®
  4. WOS: 000286703300005

Library Notes

  1. Fiscal Year: FY2010-2011
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