title: Activation of Erk and p53 regulates copper oxide nanoparticle-induced cytotoxicity in keratinocytes and fibroblasts.
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.
authors.affiliation: Center 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, Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Center 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center 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, Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Dermatology, The 2nd Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Center 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, Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Long
authors.affiliation: Department of Dermatology, The 2nd Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Jinjing
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Dermatology, The 2nd Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Shengxiang
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Center 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, Xi'an Jiaotong University, Xi'an, People's Republic of China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D003300:Copper; D048049:Extracellular Signal-Regulated MAP Kinases; C000520:cuprous oxide
keywords: CuONP; MAPK; cell cycle arrest; cyclic pifithrin-α; nutlin-3α