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Low-concentration vemurafenib induces the proliferation and invasion of human HaCaT keratinocytes through mitogen-activated protein kinase pathway activation

Authors
 Mi Ryung Roh  ;  Jung Min Kim  ;  Sang Hee Lee  ;  Hong Sun Jang  ;  Kyu Hyun Park  ;  Kee Yang Chung  ;  Sun Young Rha 
Citation
 JOURNAL OF DERMATOLOGY, Vol.42(9) : 881-888, 2015 
Journal Title
 JOURNAL OF DERMATOLOGY 
ISSN
 0385-2407 
Issue Date
2015
MeSH
Antineoplastic Agents/adverse effects* ; Cell Line, Tumor ; Cell Proliferation/drug effects* ; Humans ; Indoles/adverse effects* ; Keratinocytes/drug effects* ; Keratinocytes/metabolism ; MAP Kinase Signaling System/drug effects* ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Melanoma/drug therapy ; Neoplasm Invasiveness ; Proto-Oncogene Proteins B-raf/genetics ; Skin Neoplasms/drug therapy ; Sulfonamides/adverse effects*
Keywords
human HaCaT keratinocyte ; matrix metalloproteinase ; mitogen-activated protein kinase pathway ; squamous cell carcinoma ; vemurafenib
Abstract
Cutaneous squamous cell carcinomas and keratoacanthomas commonly occur in patients treated with BRAF inhibitors. We investigated the effect of the BRAF inhibitor vemurafenib on normal immortalized human HaCaT keratinocytes to explore the mechanism of hyperproliferative cutaneous neoplasia associated with the use of BRAF inhibitors. Vemurafenib induced an increase in viable cell number in BRAF wild-type cell lines (SK-MEL-2 and HaCaT) but not in BRAF mutant cell lines (SK-MEL-24 and G361). In HaCaT keratinocytes, a low concentration (2 μmol/L) of vemurafenib increased cell proliferation and activated mitogen-activated protein kinase kinase/extracellular signal-regulated kinase in a CRAF-dependent manner. Invasiveness of HaCaT cells in a Matrigel assay significantly increased upon cultivation of cells with 2 μmol/L vemurafenib for 24 h. Gelatin zymography, reverse transcription polymerase chain reaction and western blot results revealed that 2 μmol/L vemurafenib treatment increased matrix metalloproteinase (MMP)-2 and MMP-9 expressions and activities in HaCaT cells. These results offer additional insight into the complex mechanism of paradoxical mitogen-activated protein kinase signaling involved in hyperproliferative cutaneous neoplasias that arise after BRAF inhibition and suggest a possible role for MMP in tumor progression and invasion.
Full Text
http://onlinelibrary.wiley.com/doi/10.1111/1346-8138.12950/abstract
DOI
10.1111/1346-8138.12950
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Roh, Mi Ryung(노미령) ORCID logo https://orcid.org/0000-0002-6285-2490
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Lee, Sang Hee(이상희)
Chung, Kee Yang(정기양) ORCID logo https://orcid.org/0000-0003-3257-0297
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/141199
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