title: Silymarin targets β-catenin signaling in blocking migration/invasion of human melanoma cells.
abstract: 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 Ser(45), Ser(33/37) and Thr(41), 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.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Mudit
authors.initials: M
authors.lastname: Vaid
authors.forename: Ram
authors.initials: R
authors.lastname: Prasad
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Katiyar
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D048128:Casein Kinase Ialpha / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D038341:Glycogen Synthase Kinases / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects*; D012838:Silymarin / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism; D014945:Wound Healing; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D012838:Silymarin; D051153:Wnt Proteins; D051176:beta Catenin; D038341:Glycogen Synthase Kinases; D048128:Casein Kinase Ialpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9