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Troglitazone inhibits histone deacetylase activity in breast cancer cells

G F Davies1, A R Ross, T G Arnason

  • 1University of Saskatchewan, Department of Anatomy and Cell Biology, Saskatoon, SK, Canada.

Cancer Letters
|August 25, 2009
PubMed

Insights

Troglitazone (TRG) and histone deacetylase inhibitors (HDACi) kill estrogen receptor-positive breast cancer cells by inhibiting HDAC activity. This leads to epigenetic changes and reduced AKT signaling, suggesting a novel cancer therapeutic strategy.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Pharmacology

Background:

  • Troglitazone (TRG), a PPARgamma agonist, previously showed efficacy against multiple drug-resistant (MDR) cancer cells when combined with Doxorubicin (DOX).
  • Estrogen receptor (ER)-positive breast cancer cells, such as MCF7, are a significant clinical challenge.

Purpose of the Study:

  • To investigate the epigenetic and cell-killing effects of TRG in ER-positive MCF7 breast cancer cells.
  • To elucidate the molecular mechanisms underlying TRG's anti-cancer activity.

Main Methods:

  • MCF7 cells were treated with Thiazolidinediones (TZDs) like TRG and Ciglitazone (CIG), a non-TZD PPARgamma agonist (15PGJ2), and histone deacetylase inhibitors (HDACi's) including Trichostatin A (TSA).
  • Cell viability was assessed using MTT assays. Western analyses and mass spectrometry were employed to evaluate epigenetic modifications.
  • HDAC activity assays were performed to determine TRG's effect on HDAC function.

Main Results:

  • TRG and HDACi treatments demonstrated a dose-dependent increase in cell killing.
  • These effects were associated with increased histone H3 acetylation (H3K9, H3K23), H2AX and H3S10 phosphorylation, and H3K79 methylation.
  • TRG inhibited HDAC activity, similar to TSA, and induced a modified HDAC1 species, suggesting ER-independent pathway involvement.
  • Both TRG and HDACi's decreased total and phosphorylated AKT levels, indicating PI3K signaling pathway downregulation.

Conclusions:

  • Troglitazone exhibits anti-cancer effects in ER-positive breast cancer cells through a mechanism involving histone deacetylase inhibition.
  • TRG's mode of action may involve the downregulation of PI3K/AKT signaling, leading to significant epigenetic alterations and cell death.
  • These findings support TRG as a potential therapeutic agent for breast cancer, possibly by modulating epigenetic landscapes.

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