Document Detail

4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3.
MedLine Citation:
PMID:  19285976     Owner:  NLM     Status:  MEDLINE    
Hyaluronan accumulation on cancer cells and their surrounding stroma predicts an unfavourable disease outcome, suggesting that hyaluronan enhances tumor growth and spreading. 4-Methylumbelliferone (4-MU) inhibits hyaluronan synthesis and retards cancer spreading in experimental animals through mechanisms not fully understood. These mechanisms were studied in A2058 melanoma cells, MCF-7 and MDA-MB-361 breast, SKOV-3 ovarian and UT-SCC118 squamous carcinoma cells by analysing hyaluronan synthesis, UDP-glucuronic acid (UDP-GlcUA) content, and hyaluronan synthase (HAS) mRNA levels. The maximal inhibition in hyaluronan synthesis ranged 22-80% in the cell lines tested. Active glucuronidation of 4-MU produced large quantities of 4-MU-glucuronide, depleting the cellular UDP-GlcUA pool. The maximal reduction varied between 38 and 95%. 4-MU also downregulated HAS mRNA levels: HAS3 was 84-60% lower in MDA-MB-361, A2058 and SKOV-3 cells. HAS2 was the major isoenzyme in MCF-7 cells and lowered by 81%, similar to 88% in A2058 cells. These data indicate that both HAS substrate and HAS2 and/or HAS3 mRNA are targeted by 4-MU. Despite different target point sensitivities, the reduction of hyaluronan caused by 4-MU was associated with a significant inhibition of cell migration, proliferation and invasion, supporting the importance of hyaluronan synthesis in cancer, and the therapeutic potential of hyaluronan synthesis inhibition.
Anne Kultti; Sanna Pasonen-Seppänen; Marjo Jauhiainen; Kirsi J Rilla; Riikka Kärnä; Emma Pyöriä; Raija H Tammi; Markku I Tammi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-03-13
Journal Detail:
Title:  Experimental cell research     Volume:  315     ISSN:  1090-2422     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-01     Completed Date:  2009-06-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1914-23     Citation Subset:  IM    
Institute of Biomedicine, Anatomy, University of Kuopio, P.O.B. 1627, FIN-70211 Kuopio, Finland.
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MeSH Terms
Base Sequence
Breast Neoplasms / drug therapy,  genetics,  metabolism
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
DNA Primers / genetics
Down-Regulation / drug effects
Glucuronosyltransferase / genetics,  metabolism*
Hyaluronic Acid / biosynthesis*
Hymecromone / analogs & derivatives*,  pharmacology
Melanoma / drug therapy,  genetics,  metabolism
Neoplasm Invasiveness / prevention & control
Neoplasms / drug therapy*,  genetics,  metabolism*
RNA, Messenger / genetics,  metabolism
RNA, Neoplasm / genetics,  metabolism
Uridine Diphosphate Glucuronic Acid / metabolism*
Reg. No./Substance:
0/4-methylumbelliferone; 0/DNA Primers; 0/RNA, Messenger; 0/RNA, Neoplasm; 2616-64-0/Uridine Diphosphate Glucuronic Acid; 90-33-5/Hymecromone; 9004-61-9/Hyaluronic Acid; EC 2.4.1.-/HAS2 protein, human; EC 2.4.1.-/HAS3 protein, human; EC

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