4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3
4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3
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DOI：
10.1016/j.yexcr.2009.03.002
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发表时间：
2009-07-01
影响因子：
3.7
通讯作者：
Tammi, Markku I.
中科院分区：
文献类型：
--
作者：
Kultti, Anne;Pasonen-Seppanen, Sanna;Tammi, Markku I.
透明质酸在癌细胞及其周围基质上的积累预示着不利的疾病结局，表明透明质酸促进肿瘤生长和扩散。在实验动物中，4- methylumbellliferone （4-MU）抑制透明质酸合成并延缓癌症扩散，其机制尚不完全清楚。通过分析透明质酸合成、udp -葡萄糖醛酸（UDP-GlcUA）含量和透明质酸合成酶（HAS） mRNA水平，在A2058黑色素瘤细胞、乳腺MCF-7和MDA-MB-361、卵巢skv -3和UT-SCC118鳞状癌细胞中研究了这些机制。对透明质酸合成的最大抑制范围为22-80%。4-MU的活性葡萄糖醛酸化产生大量的4-MU-葡萄糖醛酸，耗尽细胞内的UDP-GlcUA池。最大降幅在38%到95%之间。4-MU还下调了HAS mRNA水平：MDA-MB-361、A2058和SKOV-3细胞中的HAS3降低了84-60%。HAS2是MCF-7细胞中的主要同工酶，降低了81%，与A2058细胞中的88%相似。这些数据表明，4-MU靶向HAS底物和HAS2和/或HAS3 mRNA。尽管靶点敏感性不同，但4-MU引起的透明质酸减少与细胞迁移、增殖和侵袭的显著抑制有关，这支持了透明质酸合成在癌症中的重要性，以及透明质酸合成抑制的治疗潜力。(C) 2009爱思唯尔公司版权所有。
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. (C) 2009 Elsevier Inc. All rights reserved.