Silymarin targets β-catenin signaling in blocking migration/invasion of human melanoma cells
Authors: Ram Prasad
Santosh K Katiyar
Mudit Vaid
Qian Sun
Journal: PLoS ONE (2011)
Discipline: Multidisciplinary
Keywords: Metastatic melanoma; Wnt/β-catenin signaling pathway; silymarin; cell migration; human melanoma cell lines
Affiliations: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

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. 

Retracted: Yes

PubPeer comments:
  Following publication of this article [1], concerns were raised regarding Figure 5E. An area in the bottom right quadrant of the second panel (silymarin 10u03bcg ml) is very similar to an area in the upper left quadrant of the fourth panel (silymarin 40u03bcg ml). The University of Alabama at Birmingham confirmed that the original records and data needed to determine the validity of these experiments are not available. Following a joint investigation by the Birmingham VA Medical Center and the University of Alabama at Birmingham, the institutions requested retraction of this article, as the conclusions could not be supported by available data. In line with the institutionsu2019 investigation and recommendation, the PLOS ONE Editors retract this article based upon the unavailability of original data and records and the ambiguous identification of samples and treatments. The authors did not comment on the retraction decision. 31 Dec 2018: The PLOS ONE Editors (2018) Retraction: Silymarin Targets u03b2-Catenin Signaling in Blocking Migration Invasion of Human Melanoma Cells. PLOS ONE 13(12): e0210344. https: doi.org 10.1371 journal.pone.0210344 View retraction ,