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Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

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 seve...

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Autores principales: Kim, Geon-Hee, Fang, Xue-Quan, Lim, Woo-Jin, Park, Jooho, Kang, Tae-Bong, Kim, Ji Hyung, Lim, Ji-Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554883/
https://www.ncbi.nlm.nih.gov/pubmed/32933177
http://dx.doi.org/10.3390/ijms21186706
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author Kim, Geon-Hee
Fang, Xue-Quan
Lim, Woo-Jin
Park, Jooho
Kang, Tae-Bong
Kim, Ji Hyung
Lim, Ji-Hong
author_facet Kim, Geon-Hee
Fang, Xue-Quan
Lim, Woo-Jin
Park, Jooho
Kang, Tae-Bong
Kim, Ji Hyung
Lim, Ji-Hong
author_sort Kim, Geon-Hee
collection PubMed
description 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.
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spelling pubmed-75548832020-10-14 Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1 Kim, Geon-Hee Fang, Xue-Quan Lim, Woo-Jin Park, Jooho Kang, Tae-Bong Kim, Ji Hyung Lim, Ji-Hong Int J Mol Sci Article 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. MDPI 2020-09-13 /pmc/articles/PMC7554883/ /pubmed/32933177 http://dx.doi.org/10.3390/ijms21186706 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kim, Geon-Hee
Fang, Xue-Quan
Lim, Woo-Jin
Park, Jooho
Kang, Tae-Bong
Kim, Ji Hyung
Lim, Ji-Hong
Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1
title Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1
title_full Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1
title_fullStr Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1
title_full_unstemmed Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1
title_short Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1
title_sort cinobufagin suppresses melanoma cell growth by inhibiting lef1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554883/
https://www.ncbi.nlm.nih.gov/pubmed/32933177
http://dx.doi.org/10.3390/ijms21186706
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