Kultti Anne, Pasonen-Seppänen Sanna, Jauhiainen Marjo, Rilla Kirsi J, Kärnä Riikka, Pyöriä Emma, Tammi Raija H, Tammi Markku I
Institute of Biomedicine, Anatomy, University of Kuopio, P.O.B. 1627, FIN-70211 Kuopio, Finland.
Exp Cell Res. 2009 Jul 1;315(11):1914-23. doi: 10.1016/j.yexcr.2009.03.002. Epub 2009 Mar 13.
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.
透明质酸在癌细胞及其周围基质中的积累预示着疾病预后不良，这表明透明质酸会促进肿瘤生长和扩散。4-甲基伞形酮（4-MU）可抑制透明质酸合成，并通过尚未完全明确的机制延缓实验动物体内的癌症扩散。通过分析透明质酸合成、尿苷二磷酸葡萄糖醛酸（UDP-GlcUA）含量和透明质酸合酶（HAS）mRNA水平，在A2058黑色素瘤细胞、MCF-7和MDA-MB-361乳腺癌细胞、SKOV-3卵巢癌细胞以及UT-SCC118鳞状癌细胞中对这些机制进行了研究。在所测试的细胞系中，透明质酸合成的最大抑制率在22%至80%之间。4-MU的活性葡萄糖醛酸化产生了大量的4-MU-葡萄糖醛酸，耗尽了细胞内的UDP-GlcUA池。最大降幅在38%至95%之间。4-MU还下调了HAS mRNA水平：在MDA-MB-361、A2058和SKOV-3细胞中，HAS3降低了84%至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底物以及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相关，这支持了透明质酸合成在癌症中的重要性以及抑制透明质酸合成的治疗潜力。
