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

Wen Yu Huang, Pei Ming Yang, Yu Fan Chang, Victor E. Marquez, Ching Chow Chen

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 MTX were dependent on p53 and, partially, on p21. In addition, MTX 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 MTX acts through initiation of p53-dependent apoptosis and restoration of E-cadherin expression by downregulation of HDAC/EZH2.

Original languageEnglish
Pages (from-to)510-517
Number of pages8
JournalBiochemical Pharmacology
Volume81
Issue number4
DOIs
Publication statusPublished - Feb 15 2011
Externally publishedYes

Fingerprint

Histone Deacetylases
Cadherins
Methotrexate
Down-Regulation
Apoptosis
Tumors
Puma
Polycomb-Group Proteins
Cells
Noxae
Folic Acid Antagonists
Neoplasms
Phosphorylation
p53 Genes
Cell growth
Ribonucleases
Enhancer of Zeste Homolog 2 Protein
Heterografts
Non-Small Cell Lung Carcinoma
Restoration

Keywords

  • EZH2
  • HDAC
  • Methotrexate
  • p21
  • p53

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Methotrexate induces apoptosis through p53/p21-dependent pathway and increases E-cadherin expression through downregulation of HDAC/EZH2. / Huang, Wen Yu; Yang, Pei Ming; Chang, Yu Fan; Marquez, Victor E.; Chen, Ching Chow.

In: Biochemical Pharmacology, Vol. 81, No. 4, 15.02.2011, p. 510-517.

Research output: Contribution to journalArticle

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