Sorafenib induces pigmentation via the regulation of β‐catenin signalling pathway in melanoma cells

We conducted large‐scale screening test on drugs that were already approved for other diseases to find pigmentation‐modulating agents. Among drugs with potential for pigmentation control, we selected sorafenib and further investigated the effect on pigmentation using HM3KO melanoma cells. As a resul...

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Bibliographic Details
Published in:Experimental dermatology 2022-01, Vol.31 (1), p.57-63
Main Authors: Kim, Kyung‐Il, Jung, Kyung Eun, Shin, Young‐Bin, Kim, Chang‐Deok, Yoon, Tae‐Jin
Format: Article
Language:English
Subjects:
AKT protein
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
beta Catenin - metabolism
Catenin
Cell Line, Tumor
Drug screening
GSK3β
Humans
Intracellular signalling
Kinases
Melanin
Melanoma
Melanoma - pathology
Metabolic pathways
mRNA
Phosphorylation
Pigmentation
Pigmentation - drug effects
Signal transduction
Signal Transduction - drug effects
Skin Neoplasms - pathology
sorafenib
Sorafenib - metabolism
Sorafenib - pharmacology
Tyrosine
β‐catenin
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Summary:We conducted large‐scale screening test on drugs that were already approved for other diseases to find pigmentation‐modulating agents. Among drugs with potential for pigmentation control, we selected sorafenib and further investigated the effect on pigmentation using HM3KO melanoma cells. As a result of treating melanoma cells with sorafenib, pigmentation was promoted in terms of melanin content and tyrosinase activity. Sorafenib increased mRNA and protein levels of pigmentation‐related genes such as MITF, tyrosinase and TRP1. To uncover the action mechanism, we investigated the effect of sorafenib on the intracellular signalling pathways. Sorafenib reduced phosphorylation of AKT and ERK, suggesting that sorafenib induces pigmentation through inhibition of the AKT and ERK pathways. In addition, sorafenib significantly increased the level of active β‐catenin, together with activation of β‐catenin signalling. Mechanistic study revealed that sorafenib decreased phosphorylation of serine 9 (S9) of GSK3β, while it increased phosphorylation of tyrosine 216 (Y216) of GSK3β. These results suggest that sorafenib activates the β‐catenin signalling through the regulation of GSK3β phosphorylation, thereby affecting the pigmentation process.
ISSN:0906-6705
1600-0625
DOI:10.1111/exd.14112