Escin Activates Canonical Wnt/beta-Catenin Signaling Pathway by Facilitating the Proteasomal Degradation of Glycogen Synthase Kinase-3 beta in Cultured Human Dermal Papilla Cells

Abnormal inactivation of the Wnt/beta-catenin signaling pathway is involved in skin diseases like androgenetic alopecia, vitiligo and canities, but small-molecule activators are rarely described. In this study, we investigated the stimulatory effects of escin on the canonical Wnt/ beta-catenin signaling pathway in cultured human dermal papilla cells (hDPCs). Escin stimulated Wnt/beta-catenin signaling, resulting in increased beta-catenin and lymphoid enhancer-binding factor 1 (LEF1), the accumulation of nuclear beta-catenin and the enhanced expression of Wnt target genes in cultured hDPCs. Escin drastically reduced the protein level of glycogen synthase kinase (GSK)-3fi, a key regulator of the Wnt/ beta-catenin signaling pathway, while the presence of the proteasome inhibitor MG-132 fully restored the GSK-3 fi protein level. The treatment of secreted frizzled-related proteins (sFRPs) 1 and 2 attenuated the activity of escin in Wnt reporter assays. Our data demonstrate that escin is a natural agonist of the canonical Wnt/beta-catenin signaling pathway and downregulates GSK-3fi protein expression by facilitating the proteasomal degradation of GSK-3fi in cultured hDPCs. Our data suggest that escin likely stimulates Wnt signaling through direct interactions with frizzled receptors. This study underscores the therapeutic potential of escin for Wnt-related diseases such as androgenetic alopecia, vitiligo and canities.

Automated summary

This study found that escin can stimulate the Wnt/β-catenin signaling pathway in cultured human dermal papilla cells, resulting in increased β-catenin and LEF1 expression, accumulation of nuclear β-catenin, and enhanced expression of Wnt target genes. Additionally, escin downregulates GSK-3β protein expression by facilitating its proteasomal degradation.