Division of Urology Research, Department of Urology (M-800), University of Miami Miller School of Medicine, P.O. Box 016960, Miami, FL 33101, USA.
Cancer Res. 2010 Apr 1;70(7):2613-23. doi: 10.1158/0008-5472.CAN-09-3185. Epub 2010 Mar 23.
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 IC(50) for HA synthesis (0.4 mmol/L), 4-MU induced >3-fold apoptosis in prostate cancer cells, which could be prevented by the addition of HA. 4-MU induced caspase-8, caspase-9, and caspase-3 activation, PARP cleavage, upregulation of Fas-L, Fas, FADD and DR4, and downregulation of bcl-2, phosphorylated bad, bcl-XL, phosphorylated Akt, phosphorylated IKB, phosphorylated ErbB2, and phosphorylated epidermal growth factor receptor. At IC(50), 4-MU also caused >90% inhibition of NF-kappaB reporter activity, which was prevented partially by the addition of HA. With the exception of caveolin-1, HA reversed the 4-MU-induced downregulation of HA receptors (CD44 and RHAMM), matrix-degrading enzymes (MMP-2 and MMP-9), interleukin-8, and chemokine receptors (CXCR1, CXCR4, and CXCR7) at the protein and mRNA levels. Expression of myristoylated-Akt rescued 4-MU-induced apoptosis and inhibition of cell growth and interleukin-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 ( approximately 3-fold) and HA expression but increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells and expression of apoptosis-related molecules. Therefore, the anticancer effects of 4-MU, an orally bioavailable and relatively nontoxic agent, are primarily mediated by inhibition of HA signaling.
4-甲基伞形酮（4-MU）是一种透明质酸（HA）合成抑制剂，具有抗癌特性；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、迁移和侵袭。在透明质酸合成的 IC50（0.4mmol/L）时，4-MU 诱导前列腺癌细胞发生 >3 倍凋亡，HA 的加入可预防这种凋亡。4-MU 诱导半胱天冬酶-8、半胱天冬酶-9 和半胱天冬酶-3 激活、PARP 切割、Fas-L、Fas、FADD 和 DR4 上调以及 bcl-2、磷酸化 bad、bcl-XL、磷酸化 Akt、磷酸化 IKB、磷酸化 ErbB2 和磷酸化表皮生长因子受体下调。在 IC50 时，4-MU 还引起 >90%的 NF-κB 报告基因活性抑制，HA 的加入部分阻止了这种抑制。除了 caveolin-1 之外，HA 逆转了 4-MU 诱导的透明质酸受体（CD44 和 RHAMM）、基质降解酶（MMP-2 和 MMP-9）、白细胞介素-8 和趋化因子受体（CXCR1、CXCR4 和 CXCR7）的下调在蛋白质和 mRNA 水平上。myristoylated-Akt 的表达挽救了 4-MU 诱导的细胞凋亡以及细胞生长和白细胞介素-8、RHAMM、HAS2、CD44 和 MMP-9 表达的抑制。4-MU 的口服给药显著降低了 PC3-ML 肿瘤的生长（>3 倍），当治疗在肿瘤细胞注射当天或肿瘤可触及后开始时，没有器官毒性、血清化学变化或体重变化。4-MU 处理动物的肿瘤显示微血管密度降低（约 3 倍）和 HA 表达增加，但末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记阳性细胞和凋亡相关分子的表达增加。因此，4-MU 的抗癌作用，一种口服生物利用度高且相对无毒的药物，主要是通过抑制 HA 信号传导介导的。
