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Molecules 2014, 19(1), 159-176; doi:10.3390/molecules19010159
Article

Involvement of CUL4A in Regulation of Multidrug Resistance to P-gp Substrate Drugs in Breast Cancer Cells

1,2,†
, 1,†
, 3
, 1
, 1
, 1
, 4
, 1
, 1
, 4
 and 1,*
1 Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012, Shandong, China 2 International Biotechnology R&D Center, Shandong University School of Ocean, 180 Wenhua Xi Road, Weihai 264209, Shandong, China 3 Department of Respiratory Medicine, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan 250012, Shandong, China 4 Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012, Shandong, China These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 14 September 2013 / Revised: 15 December 2013 / Accepted: 17 December 2013 / Published: 24 December 2013
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Abstract

CUL4A encodes a core component of a cullin-based E3 ubiquitin ligase complex that regulates many critical processes such as cell cycle progression, DNA replication, DNA repair and chromatin remodeling by targeting a variety of proteins for ubiquitination and degradation. In the research described in this report we aimed to clarify whether CUL4A participates in multiple drug resistance (MDR) in breast cancer cells. We first transfected vectors carrying CUL4A and specific shCUL4A into breast cancer cells and corresponding Adr cells respectively. Using reverse transcription polymerase chain reactions and western blots, we found that overexpression of CUL4A in MCF7 and MDA-MB-468 cells up-regulated MDR1/P-gp expression on both the transcription and protein levels, which conferred multidrug resistance to P-gp substrate drugs, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. On the other hand, silencing CUL4A in MCF7/Adr and MDA-MB-468/Adr cells led to the opposite effect. Moreover, ERK1/2 in CUL4A-overexpressing cells was highly activated and after treatment with PD98059, an ERK1/2-specific inhibitor, CUL4A-induced expression of MDR1/P-gp was decreased significantly. Lastly, immunohistochemistry in breast cancer tissues showed that P-gp expression had a positive correlation with the expression of CUL4A and ERK1/2. Thus, these results implied that CUL4A and ERK1/2 participated in multi-drug resistance in breast cancer through regulation of MDR1/P-gp expression.
Keywords: multidrug resistant; P-glycoprotein; CUL4A; breast cancer multidrug resistant; P-glycoprotein; CUL4A; breast cancer
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Wang, Y.; Ma, G.; Wang, Q.; Wen, M.; Xu, Y.; He, X.; Zhang, P.; Wang, Y.; Yang, T.; Zhan, P.; Wei, G. Involvement of CUL4A in Regulation of Multidrug Resistance to P-gp Substrate Drugs in Breast Cancer Cells. Molecules 2014, 19, 159-176.

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