Suppression of ERCC1 and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human non-small cell lung cancer cells

被引:64
|
作者
Ko, Jen-Chung [2 ]
Su, Ying-Jhen [1 ]
Lin, Szu-Ting [1 ]
Jhan, Jhih-Yuan [1 ]
Ciou, Shih-Ci [1 ]
Cheng, Chao-Min [1 ]
Lin, Yun-Wei [1 ]
机构
[1] Natl Chiayi Univ, Mol Oncol Lab, Dept Biochem Sci & Technol, Chiayi, Taiwan
[2] Hsinchu Hosp, Dept Internal Med, Dept Hlth, The Executive Yuan, Taiwan
关键词
ERCC1; Rad51; Emodin; ERK1/2; Non-small cell lung cancer; NUCLEOTIDE EXCISION-REPAIR; EPIDERMAL-GROWTH-FACTOR; DNA-REPAIR; INDUCED APOPTOSIS; GENE-EXPRESSION; IONIZING-RADIATION; PROSTATE CARCINOMA; TUMOR-CELLS; IN-VITRO; RECOMBINATION;
D O I
10.1016/j.bcp.2009.09.024
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. Emodin exhibits anticancer effects against a variety of cancer cells, including lung cancer cells. ERCC1 and Rad51 proteins are essential for nucleotide excision repair and homologous recombination, respectively. Furthermore, ERCC1 and Rad51 overexpression induces resistance to DNA-damaging agents that promote DNA double-strand breaks. Accordingly, the aim of this study was to determine the role of ERCC1 and Rad51 in emodin-mediated cytotoxicity in human non-small cell lung cancer (NSCLC) cells. Both ERCC1 and Rad51 protein levels as well as mRNA levels were decreased in four different NSCLC cell lines after exposure to emodin. These decreases correlated with the inactivation of the MKK1/2-ERK1/2 pathway. Moreover, cellular ERCC1 and Rad51 protein and mRNA levels were specifically inhibited by U0126, a MKK1/2 inhibitor. We found that transient transfection of human NSCLC cells with si-ERCC1 or si-Rad51 RNA and cotreatment with U0126 could enhance emodin-induced cytotoxicity. In contrast, overexpression of constitutively active MKK1/2 vectors (MKK1/2-CA) was shown to significantly recover reduced phospho-ERK1/2, ERCC1, and Rad51 protein levels and to rescue cell viability upon emodin treatment. These results demonstrate that activation of the MKK1/2-ERK1/2 pathway is the upstream signal regulating the expressions of ERCC1 and Rad51, which are suppressed by emodin to induce cytotoxicity in NSCLC cells. Crown Copyright (C) 2009 Published by Elsevier Inc. All rights reserved.
引用
收藏
页码:655 / 664
页数:10
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