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J. Biol. Chem., Vol. 282, Issue 38, 27622-27632, September 21, 2007

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Glucosamine Hydrochloride Specifically Inhibits COX-2 by Preventing COX-2 N-Glycosylation and by Increasing COX-2 Protein Turnover in a Proteasome-dependent Manner^*

Byeong-Churl Jang¹, Su-Haeng Sung, Jong-Gu Park, Jong-Wook Park, Jae Hoon Bae, Dong Hoon Shin, Gi-Young Park, Seung-Bum Han^¶, and Seong-Il Suh²

From the Chronic Disease Research Center and Institute for Medical Science, the Department of Rehabilitation Medicine, and the ^¶Division of Pulmonology & Department of Internal Medicine, Keimyung University School of Medicine, 194 Dongsan-dong, Jung-gu, Daegu 700-712, South Korea

COX-2 and its products, including prostaglandin E₂, are involved in many inflammatory processes. Glucosamine (GS) is an amino monosaccharide and has been widely used for alternative regimen of (osteo) arthritis. However, the mechanism of action of GS on COX-2 expression remains unclear. Here we describe a new action mechanism of glucosamine hydrochloride (GS-HCl) to tackle endogenous and agonistdriven COX-2 at protein level. GS-HCl (but not GS sulfate, N-acetyl GS, or galactosamine HCl) resulted in a shift in the molecular mass of COX-2 from 72–74 to 66–70 kDa and concomitant inhibition of prostaglandin E₂ production in a concentration-dependent manner in interleukin (IL)-1-treated A549 human lung epithelial cells. Remarkably, GS-HCl-mediated decrease in COX-2 molecular mass was associated with inhibition of COX-2 N-glycosylation during translation, as assessed by the effect of tunicamycin, the protein N-glycosylation inhibitor, or of cycloheximide, the translation inhibitor, on COX-2 modification. Specifically, the effect of low concentration of GS-HCl (1 mM) or of tunicamycin (0.1 µg/ml) to produce the aglycosylated COX-2 was rescued by the proteasomal inhibitor MG132 but not by the lysosomal or caspase inhibitors. However, the proteasomal inhibitors did not show an effect at 5 mM GS-HCl, which produced the aglycosylated or completely deglycosylated form of COX-2. Notably, GS-HCl (5 mM) also facilitated degradation of the higher molecular species of COX-2 in IL-1-treated A549 cells that was retarded by MG132. GS-HCl (5 mM) was also able to decrease the molecular mass of endogenous and IL-1- or tumor necrosis factor--driven COX-2 in different human cell lines, including Hep2 (bronchial) and H292 (laryngeal). However, GS-HCl did not affect COX-1 protein expression. These results demonstrate for the first time that GS-HCl inhibits COX-2 activity by preventing COX-2 co-translational N-glycosylation and by facilitating COX-2 protein turnover during translation in a proteasome-dependent manner.

Received for publication, November 21, 2006 , and in revised form, July 16, 2007.

^* This work was supported by Grant R13-2002-028-02001-0 from the Basic Research Program of Korea Science and Engineering Foundation to the Chronic Disease Research Center at Keimyung University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. Tel.: 82-53-250-7032; Fax: 82-53-250-8005; E-mail: jangbc12{at}kmu.ac.kr. ² To whom correspondence may be addressed. Tel.: 82-53-250-7442; Fax: 82-53-255-1398; E-mail: seong{at}dsmc.or.kr.

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