Roles of SIRT1 and phosphoinositide 3-OH kinase/protein kinase C pathways in evodiamine-induced human melanoma A375-S2 cell death

J Pharmacol Sci. 2005 Apr;97(4):494-500. doi: 10.1254/jphs.fpj04055x. Epub 2005 Apr 9.

Abstract

We previously demonstrated that evodimine isolated from Evodia rutaecarpa (Goshuyu in Japan) induced apoptosis in human malignant melanoma A375-S2 cells within 24 h. In this study, TUNEL assay also indicated that one cause of A375-S2 cell death induced by evodiamine was apoptosis. After treatment with evodiamine for the indicated time periods, anti-apoptotic protein SIRT1 expression was decreased; p53 expression and its phosphorylation were both enhanced, whereas transient induction of downstream p21 was not enough to promote cell cycle arrest. Inhibition of the phosphoinositide 3-OH kinase (PI3-K)/protein kinase C (PKC) survival pathway as well as subsequent inhibition of the ERK cascade might contribute to evodiamine-induced cell death. In addition, p53 activation in response to evodiamine administration was correlated with the activation of the PI3-K/PKC pro-apoptotic pathway, but did not require ERK participation. The inhibition of the PI3-K/PKC survival pathway might be responsible for SIRT1 inactivation and increased Bax/Bcl-2 expression ratio in evodiamine-induced cell death.

MeSH terms

  • Androstadienes / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology
  • Evodia
  • Gene Expression / drug effects
  • Genes, p53 / drug effects
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / metabolism*
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phytotherapy*
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Signal Transduction / drug effects
  • Sirtuin 1
  • Sirtuins / antagonists & inhibitors
  • Sirtuins / metabolism*
  • Staurosporine / pharmacology
  • Wortmannin
  • bcl-2-Associated X Protein

Substances

  • Androstadienes
  • BAX protein, human
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Plant Extracts
  • Proto-Oncogene Proteins c-bcl-2
  • Quinazolines
  • bcl-2-Associated X Protein
  • evodiamine
  • Protein Kinase C
  • SIRT1 protein, human
  • Sirtuin 1
  • Sirtuins
  • Histone Deacetylases
  • Staurosporine
  • Wortmannin