Oncotarget

Research Papers:

Cefradine blocks solar-ultraviolet induced skin inflammation through direct inhibition of T-LAK cell-originated protein kinase

Xiaoming Fan _, Qiuhong Duan, Changshu Ke, Guiping Zhang, Juanjuan Xiao, Dan Wu, Xiaoyu Zeng, Jingwen Chen, Jinguang Guo, Jie Zhou, Fei Shi and Feng Zhu

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Oncotarget. 2016; 7:24633-24645. https://doi.org/10.18632/oncotarget.8260

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Abstract

Xiaoming Fan1,*, Qiuhong Duan1,*, Changshu Ke2, Guiping Zhang3, Juanjuan Xiao1, Dan Wu1, Xiaoyu Zeng1, Jingwen Chen4, Jinguang Guo4, Jie Zhou1, Fei Shi4, Feng Zhu1

1Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China

2Department of Pathology, Tongji hospital, Huazhong University of Science and Technology, Wuhan, 430030, PR China

3Shanghai Biyi Chemical Science and Technology Co., Shanghai, 201203, PR China

4Department of Dermatology of the General Hospital of Air Force, Beijing, 100142, PR China

*These authors have contributed equally to this work

Correspondence to:

Jie Zhou, e-mail: chentianyuzj@163.com

Fei Shi, e-mail: shf_1969@163.com

Feng Zhu, e-mail: fengzhu@hust.edu.cn

Keywords: cefradine, TOPK, signal transduction pathway, solar UV, skin inflammation

Received: November 16, 2015    Accepted: March 07, 2016    Published: March 22, 2016

ABSTRACT

Skin inflammation, and skin cancer induced by excessive solar ultraviolet (SUV) is a great threat to human health. SUV induced skin inflammation through activating p38 mitogen-activated protein kinase (p38) and c-Jun N-termeinal kinases (JNKs). T-LAK cell-originated protein kinase (TOPK) plays an important role in this process. Herein, the clinical data showed TOPK, phospho-p38, phospho-JNKs were highly expressed in human solar dermatitis. Ex vivo studies showed that SUV induced the phosphorylation of p38 and JNKs in HaCat and JB6 cells in a dose and time dependent manner. Molecule docking model indicated cefradine, an FDA-approved cephalosporin antibiotic, directly binds with TOPK. The result of in vitro binding assay verified cefradine can directly bind with TOPK. In vitro kinase results showed cefradine can inhibit TOPK activity. Ex vivo studies further showed cefradine inhibited SUV-induced the phosphorylation level of p38, JNKs and H2AX through inhibiting TOPK activity in a dose and time dependent manner, and cefradine inhibited the secretion of IL6 and TNF-α in HaCat and JB6 cells. In vivo studies showed that cefradine down-regulated SUV-induced the phosphorylation of p38, JNKs and H2AX and inhibited the secretion of IL6 and TNF-α in Babl/c mice. These results indicated that cefradine can inhibit SUV-induced skin inflammation by blocking TOPK signaling pathway, and TOPK is an effective target for suppressing inflammation induced by SUV irradiation.


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