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Ras/MAP kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate

Ji-Won Jung1, Sung-Dae Cho, Nam-Shik Ahn

  • 1Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.

Cancer Letters
|June 28, 2005
PubMed

Insights

Sodium butyrate (NaBu) induces apoptosis in ras-transformed liver cells by inhibiting the ras/ERK pathway. This histone deacetylase inhibitor shows promise as a cancer therapeutic, affecting key cell signaling proteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Histone deacetylase inhibitors (HDACi) like sodium butyrate (NaBu) are emerging cancer therapeutics.
  • Ras-transformed cells are a model for studying cancer progression and therapeutic responses.

Purpose of the Study:

  • To investigate the specific mechanisms by which NaBu induces apoptosis in ras-transformed rat liver epithelial (WB-ras) cells.
  • To elucidate the role of signaling pathways, particularly ras/raf/MEK/ERK and p38 MAP kinase, in NaBu-induced apoptosis.

Main Methods:

  • Treatment of WB-ras cells with NaBu and analysis of apoptosis.
  • Western blotting to assess protein expression levels (ras, ERK1/2, p38 MAP kinase, p53, p21CIP1/WAF1, cdk2, cdk4, Akt).
  • Use of specific inhibitors: sodium orthovanadate (SOV) and SB203580.

Main Results:

  • NaBu treatment induced significant apoptosis in WB-ras cells within 48 hours.
  • Inhibition of ras proteins (especially farnesylated ras) and down-regulation of ERK1/2 were observed, alongside sustained p38 MAP kinase upregulation.
  • Upregulation of pro-apoptotic proteins (p53, p21CIP1/WAF1) and downregulation of cell cycle/anti-apoptotic proteins (cdk2, cdk4, p-Akt) occurred.
  • Sodium orthovanadate blocked apoptosis and restored protein levels, while the p38 inhibitor SB203580 had minimal effect.

Conclusions:

  • NaBu induces apoptosis in ras-transformed liver cells through a mechanism involving the ras/ERK signaling pathway.
  • The ras/ERK pathway is a relevant target for NaBu-based chemotherapeutic strategies, independent of its histone deacetylase inhibitory activity.
  • Modulation of specific apoptotic and cell cycle regulatory proteins contributes to NaBu's anti-cancer effects.

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