Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells.
Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells.
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DOI：
10.1158/0008-5472.can-09-3185
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Altman N
中科院分区：
文献类型：
--
作者：
Lokeshwar VB;Lopez LE;Munoz D;Chi A;Shirodkar SP;Lokeshwar SD;Escudero DO;Dhir N;Altman N
4-methylumbelliferone (4-MU) 是一种具有抗癌特性的透明质酸 (HA) 合成抑制剂；其抗癌作用的机制尚不清楚。我们评估了 4-MU 对前列腺癌细胞的影响。 4-MU 抑制 DU145、PC3-ML、LNCaP、C4-2B 和/或 LAPC-4 细胞的增殖、运动和侵袭。在 HA 合成的 IC50 (0.4 mM) 下，4-MU 诱导前列腺癌细胞 3 倍以上的细胞凋亡，这可以通过添加 HA 来预防。 4-MU 诱导 caspase-8、-9 和 -3 激活、PARP 裂解、Fas-L、Fas、FADD 和 DR4 上调以及 bcl-2、磷酸-bad、bcl-XL、磷酸-Akt、磷酸-IKB、磷酸-ErbB2 和磷酸-EGFR 下调。在 IC50 时，4-MU 还对 NFkB 报告基因活性产生 > 90% 的抑制，但添加 HA 可以部分阻止这种抑制。除Caveolin-1外，HA可防止4-MU诱导的HA受体（CD44、RHAMM）、基质降解酶（MMP-2、MMP-9）、IL-8和趋化因子受体（CXCR1、CXCR4、CXCR7）在蛋白质和mRNA水平上的下调。肉豆蔻酰化-Akt 的表达可挽救 4-MU 诱导的细胞凋亡并抑制细胞生长以及 IL-8、RHAMM、HAS2、CD44 和 MMP-9 表达。当在肿瘤细胞注射当天或肿瘤变得明显后开始治疗时，口服4-MU可显着降低PC3-ML肿瘤生长（> 3倍），且无器官毒性、血清化学或体重变化。 4-MU 治疗动物的肿瘤显示微血管密度降低（约 3 倍）和 HA 表达，但 TUNEL 阳性细胞和凋亡相关分子的表达增加。因此，4-MU（一种口服生物可利用且相对无毒的药物）的抗癌作用主要是通过抑制 HA 信号传导来介导的。
4-methylumbelliferone (4-MU) is a hyaluronic acid (HA) synthesis inhibitor with anticancer properties; the mechanism of its anticancer effects is unknown. We evaluated the effects of 4-MU on prostate cancer cells. 4-MU inhibited proliferation, motility and invasion of DU145, PC3-ML, LNCaP, C4-2B and/or LAPC-4 cells. At IC50 for HA synthesis (0.4 mM), 4-MU induced > 3-fold apoptosis in prostate cancer cells, which could be prevented by HA addition. 4-MU induced caspase-8, -9 and -3 activation, PARP cleavage, up-regulation of Fas-L, Fas, FADD and DR4 and down regulation of bcl-2, phospho-bad, bcl-XL, phospho-Akt, phospho-IKB, phospho-ErbB2 and phospho-EGFR. At IC50, 4-MU also caused > 90% inhibition of NFkB reporter activity which was prevented partially by HA addition. With the exception of caveolin-1, HA prevented the 4-MU induced down regulation of HA receptors (CD44, RHAMM), matrix-degrading enzymes (MMP-2, MMP-9), IL-8, and chemokine receptors (CXCR1, CXCR4, CXCR7) at protein and mRNA levels. Expression of myristoylated-Akt rescued 4-MU induced apoptosis and inhibition of cell growth and IL-8, RHAMM, HAS2, CD44 and MMP-9 expression. Oral administration of 4-MU significantly decreased PC3-ML tumor growth (> 3-fold), when treatment was started either on the day of tumor cell injection or after the tumors became palpable, without organ toxicity, changes in serum chemistry or body weight. Tumors from 4-MU treated animals showed reduced microvessel density (~ 3-fold) and HA expression but increased TUNEL positive cells and expression of apoptosis-related molecules. Therefore, anticancer effects of 4-MU, an orally bioavailable and relatively non-toxic agent, are primarily mediated by inhibition of HA signaling.