U0126, a mitogen-activated protein kinase kinase inhibitor, inhibits the invasion of human A375 melanoma cells
U0126, a mitogen-activated protein kinase kinase inhibitor, inhibits the invasion of human A375 melanoma cells
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DOI：
10.1016/s0304-3835(02)00004-6
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发表时间：
2002-05-28
期刊：
影响因子：
9.7
通讯作者：
Meadows, GG
中科院分区：
文献类型：
--
作者：
Ge, XK;Fu, YM;Meadows, GG
在体外检测丝裂原活化蛋白激酶（MAPK）激酶抑制剂U 0126在人A375黑素瘤细胞中的抗侵袭能力。将该效果与另一种常用的MEK（MAPK激酶）抑制剂PD 98059的效果进行比较。U 0126或PD 98059通过生长因子减少的Matrigel显示剂量依赖性地抑制A375细胞的侵袭。U 0126对肿瘤细胞侵袭的抑制作用强于PD 98059。这两种化合物显着降低尿激酶纤溶酶原激活剂（uPA）和基质金属蛋白酶-9（MMP-9）的浓度在条件培养基。在5 μ M时，U 0126在24小时内将MEK 1/2的磷酸化抑制至不可检测的水平。细胞外信号相关激酶1/2的磷酸化也被10 μ M U 0126或40 μ M PD 98059显著抑制。两种化合物均抑制c-Jun的蛋白表达，但不抑制c-Fos的蛋白表达。uPA和MMP-9的表达也受到抑制。我们的数据表明，U 0126是一种有效的药物，在抑制人A375黑色素瘤细胞的侵袭和效果是部分由于减少生产的uPA和MMP-9。(C)2002爱思唯尔科学爱尔兰有限公司保留所有权利。
The anti-invasive ability of the mitogen-activated protein kinase (MAPK) kinase inhibitor, U0126, was examined in human A375 melanoma cells in vitro. The effect was compared to that of PD98059, another commonly used MEK (MAPK kinase) inhibitor. U0126 or PD98059 showed a dose-dependent inhibition of A375 cell invasion through growth factor-reduced Matrigel. U0126 was more potent than PD98059 in suppressing tumor cell invasion. Both compounds significantly decreased urokinase plasminogen activator (uPA) and matrix metalloproteinases-9 (MMP-9) concentrations in conditioned media. At 5 muM, U0126 inhibited phosphorylation of the MEK 1/2 to a non-detectable level within 24 h. The phosphorylation of extracellular signal-related kinase 1/2 was also dramatically suppressed by the treatment with 10 muM U0126 or 40 muM PD98059. Both compounds suppressed the protein expression of c-Jun, but not c-Fos. The expression of uPA and MMP-9 was also inhibited. Our data suggest that U0126 is an effective agent in inhibiting human A375 melanoma cell invasion and that the effect is partially due to the decreased production of uPA and MMP-9. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.