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Methotrexate induces apoptosis through p53/p21-dependent pathway and increases E-cadherin expression through

Wen-Yu Huang1, Pei-Ming Yang, Yu-Fan Chang

  • 1Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan.

Biochemical Pharmacology
|December 1, 2010
PubMed

Insights

Methotrexate (MTX) effectively combats non-small cell lung cancer (NSCLC) by triggering programmed cell death (apoptosis) and restoring E-cadherin expression. This anticancer action is mediated through p53 activation and inhibition of HDAC/EZH2 pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Methotrexate (MTX) is a dihydrofolate reductase (DHFR) inhibitor utilized in cancer chemotherapy.
  • Non-small cell lung cancer (NSCLC) remains a significant global health challenge.
  • Understanding the precise molecular mechanisms of MTX in NSCLC is crucial for optimizing treatment strategies.

Purpose of the Study:

  • To elucidate the anti-tumor mechanisms of Methotrexate (MTX) in non-small cell lung cancer (NSCLC) A549 cells.
  • To investigate the role of p53 and E-cadherin in MTX-induced anti-cancer effects.
  • To explore the impact of MTX on epigenetic regulators like HDAC and EZH2.

Main Methods:

  • In vitro cell growth inhibition assays and apoptosis induction studies.
  • Animal xenograft models to assess in vivo tumor formation.
  • RNase protection assay (RPA) and RT-PCR to analyze gene expression.
  • Western blotting to evaluate protein phosphorylation and acetylation.

Main Results:

  • MTX inhibited NSCLC A549 cell growth and tumor formation in vivo.
  • MTX induced apoptosis via upregulation of p53 target genes (DR5, p21, Puma, Noxa).
  • MTX promoted p53 stability and expression through phosphorylation and acetylation.
  • MTX increased E-cadherin expression by inhibiting HDAC activity and downregulating EZH2.

Conclusions:

  • MTX exhibits anti-cancer effects in NSCLC through p53-dependent apoptosis induction.
  • MTX restores E-cadherin expression by modulating HDAC/EZH2 pathways.
  • The findings provide insights into MTX's therapeutic potential and mechanisms in NSCLC treatment.

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