Ursolic acid induces Bax-dependent apoptosis through the caspase-3 pathway in endometrial cancer SNG-II cells

Oncol Rep. 2005 Jan;13(1):51-7.

Abstract

The goal of this study was to examine the effect of ursolic acid, a pentacyclic triterpenoid compound, on growth of the endometrial cancer cell line SNG-II. We found that ursolic acid strongly inhibited the growth of SNG-II cells in a dose- and time-dependent manner. Morpholgical changes characteristic of apoptosis were observed in treated cells, such as the presence of apoptotic bodies and fragmentation of DNA into oligonucleosomal-sized fragments. We also investigated the active forms of caspase-3, -8 and -9 in ursolic acid-treated SNG-II cells. At 25 and 50 microM strength, ursolic acid induced marked increases in caspase-3 activity to approximately 5-fold that of control cells. Levels of cleaved caspase-3 increased in a time- and dose-dependent manner. Activation of caspases also led to the cleavage of target proteins, such as PARP. Ursolic acid treatment also resulted in a cleavage of poly (ADP-ribose) polymerase in a dose-dependent manner. Testing whether caspase-3 activation and DNA polymerase activity were inhibited by addition of Ac-DEDV-HCO during ursolic acid treatment showed that 50 microM Ac-DEDV-HCO inhibited caspase-3 activity in treated cells. Although DNA fragmentation was observed after ursolic acid treatment, DNA fragmentation did not occur in SNG II cells treated with both Ac-DEDV-HCO and ursolic acid. Because some researchers have suggested that mitochondrial pathways are involved in ursolic acid-induced apoptosis secondary to induction of mitochondrial cytochrome c release, we studied mitochondrial events in ursolic acid-induced apoptosis in these cell lines. After ursolic acid treatment, the anti-apoptotic Bcl-2 protein decreased and Bax expression was enhanced. Our results indicated that ursolic acid induced apoptotic processes in the endometrial cancer SNG-II cell line through mechanisms involving mitochondrial pathways and Bcl-2 family proteins.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis*
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Line, Tumor
  • Cytochromes c / metabolism
  • DNA / drug effects
  • DNA Fragmentation
  • Endometrial Neoplasms / metabolism*
  • Female
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Oligopeptides / pharmacology
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Triterpenes / pharmacology*
  • Up-Regulation
  • Ursolic Acid
  • bcl-2-Associated X Protein

Substances

  • Antineoplastic Agents, Phytogenic
  • BAX protein, human
  • Caspase Inhibitors
  • Oligopeptides
  • Proto-Oncogene Proteins c-bcl-2
  • Triterpenes
  • acetyl-aspartyl-glutamyl-valyl-aspartal
  • bcl-2-Associated X Protein
  • Cytochromes c
  • DNA
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • Caspase 3
  • Caspases