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J. Biol. Chem., Vol. 279, Issue 32, 33281-33289, August 6, 2004

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A Novel Mechanism for the Inhibition of Hyaluronan Biosynthesis by 4-Methylumbelliferone^*

Ikuko Kakizaki, Kaoru Kojima, Keiichi Takagaki, Masahiko Endo, Reiji Kannagi¶, Masaki Ito||, Yoshihiro Maruo**, Hiroshi Sato, Tadashi Yasuda, Satoka Mita¶¶, Koji Kimata, and Naoki Itano||||

From the Department of Biochemistry, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Program of Molecular Pathology, Aichi Cancer Center, Research Institute, Nagoya 464-8681, ^¶Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, ^||Second Department of Internal Medicine, the ^**Department of Pediatrics and the Department of Biology, Shiga University of Medical Science, Seta, Otsu, Shiga, the ^¶¶Department of Biochemistry, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, and Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan

Specific inhibitors of hyaluronan (HA) biosynthesis can be valuable therapeutic agents to prevent cancer invasion and metastasis. We have found previously that 4-methylumbelliferone (MU) inhibits HA synthesis in human skin fibroblasts and in group C Streptococcus. In this paper, the inhibition mechanism in mammalian cells was investigated using rat 3Y1 fibroblasts stably expressing HA synthase (HAS) 2. Exposure of the transfectants to the inhibitor resulted in significant reduction of HA biosynthesis and matrix formation. The evaluation of HAS transcripts and analysis of cell-free HA synthesis demonstrated the post-transcriptional suppression of HAS activity by MU. Most interesting, the post-transcriptional suppression of HAS activity was also observed using p-nitrophenol, a well known substrate for UDP-glucuronyltransferases (UGT). We investigated whether the inhibition was exerted by the glucuronidation of MU using both high pressure liquid chromatography and TLC analyses. The production of MU-glucuronic acid (GlcUA) was consistent with the inhibition of HA synthesis in HAS transfectants. MU-GlcUA was also detected at a similar level in control cells, suggesting that the glucuronidation was mediated by an endogenous UGT. Elevated levels of UGT significantly enhanced the inhibitory effects of MU. In contrast, the inhibition by MU was diminished to the control level when an excess of UDP-GlcUA was added to the cell-free HA synthesis system. We propose a novel mechanism for the MU-mediated inhibition of HA synthesis involving the glucuronidation of MU by endogenous UGT resulting in a depletion of UDP-GlcUA.

Received for publication, May 27, 2004

^* This work was supported by grants from the CREST of Japan Science and Technology Agency, a preparatory grant for research at the Division of Matrix Glycoconjugates, Research Center for Infectious Disease, Aichi Medical University, grants-in-aid for young scientists (B), Grants-in-aid for Scientific Research on Priority Areas from the Japan's Ministry of Education, Culture, Sports, Science, and Technology 14780480 and 15040203, Grant-in-aid for Scientific Research (B) from Japan Society for the Promotion of Science 15370041, the Aichi Cancer Research Foundation, grant-in-aid from the Tokyo Biochemical Research Foundation, special research funds from Seikagaku Corp., and the Karoji Memorial Fund for Medical Research (A) and (B) in Hirosaki University. The costs of publication of this article were de-frayed 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.

^|||| To whom correspondence should be addressed. Tel.: 81-52-264-4811 (ext. 2095); Fax: 81-561-63-3532; E-mail: itano{at}amugw.aichi-medu.ac.jp.

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