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PLoS By Category | Recent
PLoS Articles
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Dermatology - Oncology
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Silymarin Targets ß-Catenin Signaling in Blocking Migration/Invasion of Human Melanoma Cells
Published:
Thursday, July 28, 2011
Author:
Mudit Vaid et al.
by Mudit Vaid, Ram Prasad, Qian Sun, Santosh K. Katiyar
Metastatic melanoma is a leading cause of death from skin diseases, and is often associated with activation of Wnt/ß-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/ß-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 ß-catenin, while reducing the nuclear accumulation of ß-catenin (i.e., ß-catenin inactivation) and reducing the levels of matrix metalloproteinase (MMP) -2 and MMP-9 which are the down-stream targets of ß-catenin. Silymarin enhanced: (i) the levels of casein kinase 1a, glycogen synthase kinase-3ß and phosphorylated-ß-catenin on critical residues Ser45, Ser33/37 and Thr41, and (ii) the binding of ß-transducin repeat-containing proteins (ß-TrCP) with phospho forms of ß-catenin in melanoma cells. These events play important roles in degradation or inactivation of ß-catenin. To verify whether ß-catenin is a potent molecular target of silymarin, the effect of silymarin was determined on ß-catenin-activated (Mel 1241) and ß-catenin-inactivated (Mel 1011) melanoma cells. Treatment of Mel 1241 cells with silymarin or FH535, an inhibitor of Wnt/ß-catenin pathway, significantly inhibited cell migration of Mel 1241 cells, which was associated with the elevated levels of casein kinase 1a and glycogen synthase kinase-3ß, and decreased accumulation of nuclear ß-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 ß-catenin signaling pathway.
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