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Cyclooxygenase-2 inhibits novel ginseng metabolite-mediated apoptosis

Cited 39 time in Web of Science Cited 48 time in Scopus

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
American Association for Cancer Research
Cancer Research, Vol.65 No.5, pp.1952-1960
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.
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  • College of Medicine
  • Department of Medicine
Research Area Clinical Medicine


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