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Cyclooxygenase-2 Inhibits Novel Ginseng Metabolite-Mediated Apoptosis

¹ National Research Laboratory for Cancer Epigenetics, Cancer Research Institute and ² Department of Internal Medicine, Seoul National University College of Medicine, Chongno, Seoul, Republic of Korea

Requests for reprints: Yung-Jue Bang or Hyun-Soon Jong, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Ko, Seoul 110-744, Republic of Korea. Phone: 82-2-2072-2390; Fax: 82-2-2072-9662; E-mail: bangyj{at}plaza.snu.ac.kr or hsjong{at}snu.ac.kr.

Recently, a novel intestinal bacterial metabolite of ginseng protopanaxadiol saponins, i.e., 20-O-(ß-D-glucopyranosyl)-20(S)-protopanaxadiol (IH-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 µmol/L led to both apoptotic cell death and G₁ arrest in Hep3B cells, but only resulted in G₁ arrest in MDA-MB-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 IH-901-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 G₁ 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 G₁ arrest and apoptosis, and this apoptosis could be inhibited by COX-2 induction.

Key Words: IH-901 • apoptosis • COX-2 • siRNAs • p27^Kip1

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