Constitutive activation of the β-
catenin dependent canonical Wnt signaling pathway, which enhances
tumor growth and progression in multiple types of
cancer, is commonly observed in
melanoma. LEF1 activates β-
catenin/TCF4 transcriptional activity, promoting
tumor growth and progression. Although several reports have shown that LEF1 is highly expressed in
melanoma, the functional role of LEF1 in
melanoma growth is not fully understood. While A375, A2058, and G361
melanoma cells exhibit abnormally high LEF1 expression,
lung cancer cells express lower LEF1 levels. A
luciferase assay-based high throughput screening (HTS) with a natural compound library showed that
cinobufagin suppressed β-
catenin/TCF4 transcriptional activity by inhibiting LEF1 expression.
Cinobufagin decreases LEF1 expression in a dose-dependent manner and Wnt/β-
catenin target genes such as Axin-2,
cyclin D1, and c-Myc in
melanoma cell lines.
Cinobufagin sensitively attenuates cell viability and induces apoptosis in LEF1 expressing
melanoma cells compared to LEF1-low expressing
lung cancer cells. In addition, ectopic LEF1 expression is sufficient to attenuate
cinobufagin-induced apoptosis and cell growth retardation in
melanoma cells. Thus, we suggest that
cinobufagin is a potential anti-
melanoma drug that suppresses
tumor-promoting Wnt/β-
catenin signaling via LEF1 inhibition.