期刊
BIOLOGICAL & PHARMACEUTICAL BULLETIN
卷 35, 期 7, 页码 1022-1028出版社
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.b110660
关键词
ursolic acid; SK-OV-3; apoptosis; caspase; astrocyte elevated gene-1; glycogen synthase kinase 3 beta
资金
- Korea Science and Engineering Foundation (KOSEF)
- Korea government (MEST) [2012-0005755]
- Biogreen project [PJ0077998]
- National Research Foundation of Korea [2009-0063674] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Rural Development Administration (RDA), Republic of Korea [PJ007998012012] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Although ursolic acid isolated from Oldenlandia diffusa (Rubiaceae) was known to have anticancer activities in prostate, breast and liver cancers, the underlying mechanism of ursolic acid in ovarian cancer cells was not investigated so far. In the present study, the apoptotic mechanism of ursolic acid was elucidated in SK-OV-3 ovarian cancer cells by 2,3-bis(2-methoxy-4-nitro-5-sulphophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay, cell cycle analysis and Western blotting. Ursolic acid exerted cytotoxicity against SK-OV-3 and A2780 ovarian cancer cells with IC50 of ca. 50 and 65 mu M, respectively. Apoptotic bodies were observed in ursolic acid treated SK-OV-3 cells. Also, ursolic acid significantly increased ethidium homodimer stained cells and sub-G1 apoptotic portion in SK-OV-3 cells. Consistently, Western blotting revealed that ursolic acid effectively cleaved poly(ADP-ribose) polymerase (PARP), caspase-9 and -3, suppressed the expression of survival genes such as c-Myc, Bcl-x(L) and astrocyte elevated gene (AEG)-1, and upregulated phosphorylation of extracellular signal-regulated kinase (ERK) in SK-OV-3 cells. Interestingly, ursolic acid suppressed beta-catenin degradation as well as enhanced phosphorylation of glycogen synthase kinase 3 beta (GSK 3 beta). Furthermore, GSK 3 beta inhibitor SB216763 blocked the cleavages of caspase-3 and PARP induced by ursolic acid and proteosomal inhibitor MG132 disturbed down-regulation of beta-catenin, activation of caspase-3 and decreased mitochondrial membrane potential (MMP) induced by ursolic acid in SK-OV-3 cells. Overall, our findings suggest that ursolic acid induces apoptosis via activation of caspase and phosphorylation of GSK 3 beta in SK-OV-3 cancer cells as a potent anti-cancer agent for ovarian cancer therapy.
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