Silymarin targets β-catenin signaling in blocking migration/invasion of human melanoma cells.
Silymarin targets β-catenin signaling in blocking migration/invasion of human melanoma cells.
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DOI：
10.1371/journal.pone.0023000
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Katiyar SK
中科院分区：
文献类型：
--
作者：
Vaid M;Prasad R;Sun Q;Katiyar SK
转移性黑色素瘤是导致皮肤病死亡的主要原因之一，常与Wnt/β-Catenin信号通路激活有关。我们检测了水飞蓟素对转移特异性人黑色素瘤细胞系(A375和Hs294t)细胞迁移的抑制作用，并探讨了Wnt/β-catenin信号通路是否是水飞蓟素作用的靶点。通过体外侵袭实验，我们发现水飞蓟素对人黑色素瘤细胞株的迁移有浓度依赖性的抑制作用，这与细胞内β-连环蛋白的积聚有关，同时减少了β-连环蛋白的核积聚(即β-连环蛋白失活)，并降低了作为β-连环蛋白下游靶点的基质金属蛋白酶-2和基质金属蛋白酶-9的水平。水飞蓟素增强了黑色素瘤细胞中酪蛋白激酶1α、糖原合成酶β和关键残基Ser45、Ser33/37和Thr41上的磷酸化β-连环蛋白的水平，以及(Ii)黑色素瘤细胞中β-转导蛋白重复序列蛋白(β-TrCP)与磷酸形式的β-连环蛋白的结合。这些事件在β-连环蛋白的降解或失活过程中起着重要作用。为了验证β-连环蛋白是否是水飞蓟素的有效分子靶点，测定了水飞蓟素对β-连环蛋白激活的(MEL1241)和β-连环蛋白灭活的(MEL1011)黑色素瘤细胞的作用。水飞蓟素或WNT/β-连环蛋白通路阻断剂FH535处理MEL1241细胞后，细胞迁移受到明显抑制，其机制可能与酪蛋白激酶1α和糖原合成酶β表达升高、核β-连环蛋白积聚减少以及MMP2和MMP9表达受抑制有关。然而，水飞蓟素和FH535在Mel 1011黑色素瘤细胞中没有发现这种作用。这些结果首次表明水飞蓟素通过靶向β-连环蛋白信号通路抑制黑色素瘤细胞的迁移。
Metastatic melanoma is a leading cause of death from skin diseases, and is often associated with activation of Wnt/β-catenin signaling pathway. We have examined the inhibitory effect of silymarin, a plant flavanoid from Silybum marianum, on cell migration of metastasis-specific human melanoma cell lines (A375 and Hs294t) and assessed whether Wnt/β-catenin signaling is the target of silymarin. Using an in vitro invasion assay, we found that treatment of human melanoma cell lines with silymarin resulted in concentration-dependent inhibition of cell migration, which was associated with accumulation of cytosolic β-catenin, while reducing the nuclear accumulation of β-catenin (i.e., β-catenin inactivation) and reducing the levels of matrix metalloproteinase (MMP) -2 and MMP-9 which are the down-stream targets of β-catenin. Silymarin enhanced: (i) the levels of casein kinase 1α, glycogen synthase kinase-3β and phosphorylated-β-catenin on critical residues Ser45, Ser33/37 and Thr41, and (ii) the binding of β-transducin repeat-containing proteins (β-TrCP) with phospho forms of β-catenin in melanoma cells. These events play important roles in degradation or inactivation of β-catenin. To verify whether β-catenin is a potent molecular target of silymarin, the effect of silymarin was determined on β-catenin-activated (Mel 1241) and β-catenin-inactivated (Mel 1011) melanoma cells. Treatment of Mel 1241 cells with silymarin or FH535, an inhibitor of Wnt/β-catenin pathway, significantly inhibited cell migration of Mel 1241 cells, which was associated with the elevated levels of casein kinase 1α and glycogen synthase kinase-3β, and decreased accumulation of nuclear β-catenin and inhibition of MMP-2 and MMP-9 levels. However, this effect of silymarin and FH535 was not found in Mel 1011 melanoma cells. These results indicate for the first time that silymarin inhibits melanoma cell migration by targeting β-catenin signaling pathway.
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