Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts

Cheng Luo,1 Yan Li,2 Liang Yang,1 Yan Zheng,3 Jiangang Long,1 Jinjing Jia,3 Shengxiang Xiao,3 Jiankang Liu1 1Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institut...

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Autores principales:	Luo C, Li Y, Yang L, Zheng Y, Long J, Jia J, Xiao S, Liu J
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2014
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/80d8a3393cb8443ca812173a55c04eb8
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spelling	oai:doaj.org-article:80d8a3393cb8443ca812173a55c04eb82021-12-02T05:10:45ZActivation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts1178-2013https://doaj.org/article/80d8a3393cb8443ca812173a55c04eb82014-10-01T00:00:00Zhttp://www.dovepress.com/activation-of-erk-and-p53-regulates-copper-oxide-nanoparticle-induced--peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013 Cheng Luo,1 Yan Li,2 Liang Yang,1 Yan Zheng,3 Jiangang Long,1 Jinjing Jia,3 Shengxiang Xiao,3 Jiankang Liu1 1Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, 2Center for Bioinformatics, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 3Department of Dermatology, The 2nd Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China Abstract: Copper oxide nanoparticles (CuONP) have attracted increasing attention due to their unique properties and have been extensively utilized in industrial and commercial applications. For example, their antimicrobial capability endows CuONP with applications in dressings and textiles against bacterial infections. Along with the wide applications, concerns about the possible effects of CuONP on humans are also increasing. It is crucial to evaluate the safety and impact of CuONP on humans, and especially the skin, prior to their practical application. The potential toxicity of CuONP to skin keratinocytes has been reported recently. However, the underlying mechanism of toxicity in skin cells has remained unclear. In the present work, we explored the possible mechanism of the cytotoxicity of CuONP in HaCaT human keratinocytes and mouse embryonic fibroblasts (MEF). CuONP exposure induced viability loss, migration inhibition, and G2/M phase cycle arrest in both cell types. CuONP significantly induced mitogen-activated protein kinase (extracellular signal-regulated kinase [Erk], p38, and c-Jun N-terminal kinase [JNK]) activation in dose- and time-dependent manners. U0126 (an inhibitor of Erk), but not SB 239063 (an inhibitor of p38) or SP600125 (an inhibitor of JNK), enhanced CuONP-induced viability loss. CuONP also induced decreases in p53 and p-p53 levels in both cell types. Cyclic pifithrin-α, an inhibitor of p53 transcriptional activity, enhanced CuONP-induced viability loss. Nutlin-3α, a p53 stabilizer, prevented CuONP-induced viability loss in HaCaT cells, but not in MEF cells, due to the inherent toxicity of nutlin-3α to MEF. Moreover, the experiments on primary keratinocytes are in accordance with the conclusions acquired from HaCaT and MEF cells. These data demonstrate that the activation of Erk and p53 plays an important role in CuONP-induced cytotoxicity, and agents that preserve Erk or p53 activation may prevent CuONP-induced cytotoxicity. Keywords: cell cycle arrest, CuONP, MAPK, nutlin-3α, cyclic pifithrin-αLuo CLi YYang LZheng YLong JJia JXiao SLiu JDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2014, Iss Issue 1, Pp 4763-4772 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Luo C Li Y Yang L Zheng Y Long J Jia J Xiao S Liu J Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts
description	Cheng Luo,1 Yan Li,2 Liang Yang,1 Yan Zheng,3 Jiangang Long,1 Jinjing Jia,3 Shengxiang Xiao,3 Jiankang Liu1 1Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, 2Center for Bioinformatics, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 3Department of Dermatology, The 2nd Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China Abstract: Copper oxide nanoparticles (CuONP) have attracted increasing attention due to their unique properties and have been extensively utilized in industrial and commercial applications. For example, their antimicrobial capability endows CuONP with applications in dressings and textiles against bacterial infections. Along with the wide applications, concerns about the possible effects of CuONP on humans are also increasing. It is crucial to evaluate the safety and impact of CuONP on humans, and especially the skin, prior to their practical application. The potential toxicity of CuONP to skin keratinocytes has been reported recently. However, the underlying mechanism of toxicity in skin cells has remained unclear. In the present work, we explored the possible mechanism of the cytotoxicity of CuONP in HaCaT human keratinocytes and mouse embryonic fibroblasts (MEF). CuONP exposure induced viability loss, migration inhibition, and G2/M phase cycle arrest in both cell types. CuONP significantly induced mitogen-activated protein kinase (extracellular signal-regulated kinase [Erk], p38, and c-Jun N-terminal kinase [JNK]) activation in dose- and time-dependent manners. U0126 (an inhibitor of Erk), but not SB 239063 (an inhibitor of p38) or SP600125 (an inhibitor of JNK), enhanced CuONP-induced viability loss. CuONP also induced decreases in p53 and p-p53 levels in both cell types. Cyclic pifithrin-α, an inhibitor of p53 transcriptional activity, enhanced CuONP-induced viability loss. Nutlin-3α, a p53 stabilizer, prevented CuONP-induced viability loss in HaCaT cells, but not in MEF cells, due to the inherent toxicity of nutlin-3α to MEF. Moreover, the experiments on primary keratinocytes are in accordance with the conclusions acquired from HaCaT and MEF cells. These data demonstrate that the activation of Erk and p53 plays an important role in CuONP-induced cytotoxicity, and agents that preserve Erk or p53 activation may prevent CuONP-induced cytotoxicity. Keywords: cell cycle arrest, CuONP, MAPK, nutlin-3α, cyclic pifithrin-α
format	article
author	Luo C Li Y Yang L Zheng Y Long J Jia J Xiao S Liu J
author_facet	Luo C Li Y Yang L Zheng Y Long J Jia J Xiao S Liu J
author_sort	Luo C
title	Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts
title_short	Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts
title_full	Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts
title_fullStr	Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts
title_full_unstemmed	Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts
title_sort	activation of erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts
publisher	Dove Medical Press
publishDate	2014
url	https://doaj.org/article/80d8a3393cb8443ca812173a55c04eb8
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Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts

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