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

Cancer Lett. 2005 Jul 28;225(2):199-206. doi: 10.1016/j.canlet.2004.11.029. Epub 2004 Dec 18.

Abstract

Histone deacetylase inhibitors such as TSA, SAHA, and NaBu etc. are prospective cancer therapeutics of growing interest. Here, we demonstrated that oncogenic ras-transformed rat liver epithelial (WB-ras) cells were specifically undergone apoptosis by 48 h treatment of NaBu. During this, inhibition of ras proteins, especially farnesylated form of ras, and down-regulation of ERK1/2 were observed, which suggest ras/raf/MEK/ERK down-regulation, while p38 MAP kinase was maintained up-regulated. In addition, up-regulation of pro-apoptotic proteins such as p53 and p21CIP1/WAF1, and down-regulation of cell cycle regulator/anti-apoptotic proteins such as cdk2, -4 and phosphorylated Akt were observed concurrently with an increase in apoptotic cell portion. A phosphatase inhibitor, sodium orthovanadate (SOV), efficiently blocked apoptosis and restored responsible proteins for each phenomenon including ERK1/2 while SB203580, a specific p38 MAP kinase inhibitor, showed minor effect on them. Thus, ras/ERK signaling pathway can be considered in chemotherapeutic strategies of NaBu regardless of its inhibitory action on histone deacetylase.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Butyrates / antagonists & inhibitors
  • Butyrates / pharmacology*
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Gene Expression Regulation / drug effects
  • Histone Deacetylase Inhibitors
  • Imidazoles / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphorylation / drug effects
  • Pyridines / pharmacology
  • Rats
  • Signal Transduction / drug effects*
  • Substrate Specificity
  • ras Proteins / metabolism*

Substances

  • Butyrates
  • Cell Cycle Proteins
  • Histone Deacetylase Inhibitors
  • Imidazoles
  • Pyridines
  • Mitogen-Activated Protein Kinases
  • Phosphoric Monoester Hydrolases
  • ras Proteins
  • SB 203580