| 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. | |
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MedLine Citation:
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PMID: 19285976 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-03-13 |
Journal Detail:
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Title: Experimental cell research Volume: 315 ISSN: 1090-2422 ISO Abbreviation: Exp. Cell Res. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-06-01 Completed Date: 2009-06-16 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0373226 Medline TA: Exp Cell Res Country: United States |
Other Details:
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Languages: eng Pagination: 1914-23 Citation Subset: IM |
Affiliation:
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Institute of Biomedicine, Anatomy, University of Kuopio, P.O.B. 1627, FIN-70211 Kuopio, Finland. anne.kultti@uku.fi |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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 Female Glucuronosyltransferase / genetics, metabolism* Humans 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* |
| Chemical | |
Reg. No./Substance:
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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 2.4.1.17/Glucuronosyltransferase |
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