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Sequential 5-Aza 2'-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2)

Federico A Steiner1, Julie A Hong, Maria R Fischette

  • 1Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA.

Oncogene
|March 1, 2005
PubMed

Insights

Sequential treatment with 5-aza 2'-deoxycytidine (DAC) and depsipeptide FK228 (DP) induces tissue factor pathway inhibitor-2 (TFPI-2) in lung cancer cells. This induction may serve as a surrogate marker for treatment response in clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Cancer cells often exhibit altered gene expression due to epigenetic modifications like DNA methylation.
  • Tissue factor pathway inhibitor-2 (TFPI-2) can suppress cancer cell malignancy but is frequently downregulated in thoracic malignancies.
  • Understanding gene induction mechanisms is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the gene-inducing effects of sequential 5-aza 2'-deoxycytidine (DAC) and depsipeptide FK228 (DP) treatment in lung cancer cells.
  • To identify translational endpoints for clinical trials evaluating DAC and DP.
  • To explore the role of TFPI-2 as a potential biomarker for treatment response.

Main Methods:

  • cDNA arrays were utilized to analyze gene expression changes in CALU-6 and H460 lung cancer cell lines.
  • Analysis included assessment of TFPI-2 expression, promoter methylation status, and histone acetylation.
  • Drug treatments involved sequential and individual administration of DAC, DP, and PDBU, with calphostin used to investigate signaling pathways.

Main Results:

  • Sequential DAC/DP treatment robustly induced TFPI-2 expression in both tested cell lines.
  • TFPI-2 was found to be diminished or absent in a significant proportion of thoracic malignancy cell lines.
  • TFPI-2 expression loss correlated with promoter methylation in some cancer lines, while DP enhanced histone acetylation.
  • DP or PDBU alone could induce TFPI-2 in cells lacking promoter methylation, with PKC signaling involvement.

Conclusions:

  • Sequential DAC/DP administration induces TFPI-2 through cooperative mechanisms involving chromatin remodeling and PKC signaling.
  • TFPI-2 induction represents a promising preclinical rationale for combining DNA demethylating agents and HDAC inhibitors in cancer therapy.
  • TFPI-2 induction may serve as a valuable surrogate marker for monitoring treatment response in patients receiving sequential DAC/DP therapy.

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