title: Involvement of CUL4A in regulation of multidrug resistance to P-gp substrate drugs in breast cancer cells.
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.
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Wang
authors.forename: Guangxin
authors.initials: G
authors.lastname: Ma
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Mingxin
authors.initials: M
authors.lastname: Wen
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiuquan
authors.initials: X
authors.lastname: He
authors.forename: Pengju
authors.initials: P
authors.lastname: Zhang
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.forename: Taomei
authors.initials: T
authors.lastname: Yang
authors.forename: Panpan
authors.initials: P
authors.lastname: Zhan
authors.affiliation: 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. gwweisdu@gmail.com.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Wei
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D034622:RNA Interference; D014158:Transcription, Genetic
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C114234:CUL4A protein, human; D044842:Cullin Proteins