Ursolic acid induces Bax-dependent apoptosis through the caspase-3 pathway in endometrial cancer SNG-II cells.
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.
Achiwa
Yumiko
Y
Faculty of Obstetrics and Gynecology, School of Medicine, Fujita Health University, Aichi 470-1192, Japan. uda9294@fujita-hu.ac.jp
Hasegawa
Kiyosi
K
Komiya
Takasi
T
Udagawa
Yasuhiro
Y
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA / Q000187:drug effects; D053938:DNA Fragmentation; D016889:Endometrial Neoplasms / Q000378:metabolism*; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D000097245:Ursolic Acid
D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases; D045304:Cytochromes c; D004247:DNA; D009842:Oligopeptides; D011065:Poly(ADP-ribose) Polymerases; D019253:Proto-Oncogene Proteins c-bcl-2; D014315:Triterpenes; D051028:bcl-2-Associated X Protein; D000097245:Ursolic Acid; C494826:BAX protein, human; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C505407:CASP3 protein, human