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Cyclooxygenase-2 inhibits novel ginseng metabolite-mediated apoptosis

Cited 37 time in Web of Science Cited 45 time in Scopus
Authors
Yim, Hyung Woo; Jong, Hyun-Soon; Kim, Tai Young; Choi, Hyun Ho; Kim, Sang Gyun; Song, Sang Hyun; Kim, Juyong; Ko, Seong-Gyu; Lee, Jung Weon; Kim, Tae-You; Bang, Yung-Jue
Issue Date
2005-03
Publisher
American Association for Cancer Research
Citation
Cancer Research, Vol.65 No.5, pp.1952-1960
Keywords
Anti-Inflammatory Agents, Non-Steroidal/pharmacologyApoptosis/*drug effectsBreast Neoplasms/drug therapy/metabolism/pathologyCDC2-CDC28 Kinases/metabolismCarcinoma, Hepatocellular/drug therapy/metabolism/pathologyCarrier Proteins/genetics/metabolismCyclin-Dependent Kinase 2Cyclin-Dependent Kinase Inhibitor p27Cyclooxygenase 2Cyclooxygenase 2 InhibitorsCyclooxygenase Inhibitors/pharmacologyExtracellular Signal-Regulated MAP Kinases/metabolismG1 Phase/drug effectsHumansIntracellular Signaling Peptides and Proteins/genetics/metabolismLiver Neoplasms/drug therapy/metabolism/pathologyMembrane ProteinsPhosphorylation/drug effectsProstaglandin-Endoperoxide Synthases/chemistry/genetics/*metabolismProteins/metabolismRNA, Messenger/genetics/metabolismRNA, Small Interfering/pharmacologyRetinoblastoma Protein/metabolismRetinoblastoma-Like Protein p130Sapogenins/*pharmacologyTumor Cells, Cultured
Abstract
Recently, a novel intestinal bacterial metabolite of ginseng protopanaxadiol saponins, i.e., 20-0-(beta-D-glucopyranosyl)20(S)-protopanaxadiol (1H-901), has been reported to induce apoptosis in a variety of cancer cells. Here we show a differential effect of IH-901 on several cell types. Exposure to IH-901 for 48 hours at a supposedly subapoptotic concentration of 40 mumol/L led to both apoptotic cell death and G(1) arrest in Hep3B cells, but only resulted in G(1) arrest in MDAMB-231, Hs578T, and MKN28 cells. Additionally, the treatment of MDA-MB-231, but not of Hep3B, with IH-901 up-regulated cyclooxygenase-2 (COX-2) mRNA (2 hours) and protein (6 hours), and enhanced the production of prostaglandin E2. In MDA-MB-231 cells, IH=901 induced the sustained activation of extracellular signal-regulated kinase (ERK), whereas inhibition of mitogen-activated protein/ERK kinase blocked 1H901-mediated COX-2 induction and resulted in apoptosis, suggesting the involvement of an ERK-COX-2 pathway. Combined treatment with IH-901 and nonsteroidal anti-inflammatory drugs inhibited COX-2 enzyme and induced apoptosis in MDA-MB-231 and Hs578T cells. Adenovirus-mediated COX-2 small interfering RNAs also effectively inhibited COX-2 protein expression and enhanced IH-901-mediated apoptosis without inhibiting ERK 1/2 phosphorylation, thus providing direct evidence that COX-2 is an antiapoptotic molecule. Moreover, IH-901-mediated G(1) arrest resulted from an increase in p27(KiP1) mRNA and protein expression followed by a decrease in CDK2 kinase activity that was concurrent with the hypophosphorylation of Rb and p130. In conclusion, IH-901 induced both G(1) arrest and apoptosis, and this apoptosis could be inhibited by COX-2 induction.
ISSN
0008-5472
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15753395

https://hdl.handle.net/10371/29689
DOI
https://doi.org/10.1158/0008-5472.CAN-04-1740
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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