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Papers In Press, published online ahead of print June 9, 2004
Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195
Corresponding Author: itano{at}amugw.aichi-med-u.ac.jp
Specific inhibitors of hyaluronan (HA) biosynthesis can be valuable therapeutic agents to prevent cancer invasion and metastasis. We have previously found 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 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 posttranscriptional suppression of HAS activity by MU. Interestingly, the posttranscriptional 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 HPLC and TLC analyses. The production of MU-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.
J. Biol. Chem, 10.1074/jbc.M405918200
Submitted on May 27, 2004
Revised on June 9, 2004
Accepted on June 9, 2004
A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone
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