title: Survivin up-regulates the expression of breast cancer resistance protein (BCRP) through attenuating the suppression of p53 on NF-κB expression in MCF-7/5-FU cells.
abstract: Both breast cancer resistance protein (BCRP, ABCG2) and apoptosis-related molecules are involved in the development of multidrug resistance (MDR) in cancer cells. However, the association of BCRP with apoptosis-related molecules in the development of MDR is unknown. In this study, we investigated the changes in expression levels of BCRP, Survivin, p53, Bcl-2, Bcl-xL or Bax in cultured MCF-7 and MCF-7/5-FU cells, and explored whether these changes affected the expressions of BCRP. Our data showed that the protein and mRNA expression levels of BCRP, Survivin and Bcl-2 were significantly higher in MCF-7/5-FU cells than in MCF-7 cells, while p53 expression lower in MCF-7/5-FU cells than in MCF-7 cells. Knockdown of Survivin or Bcl-2 in MCF-7/5-FU cells and overexpression of Survivin in MCF-7 cells revealed that Survivin had significant association with BCRP expression. Luciferase reporter gene assays showed that Survivin up-regulated BCRP expression at transcriptional level and this response was mediated through NF-κB(p50) pathway. However, may be due to the physical interaction between p53 and Survivin, p53 directly affected Survivin-regulated BCRP expressions. Interestingly, we found that Survivin would suppress p53 expression. Furthermore, our data revealed that Survivin itself had no apparent effect on NF-κB(p50) and BCRP expression when knockdown of p53 in MCF-7 cells; whereas p53 exerted significant inhibitory action on these when knockdown of Survivin. In conclusion, through down regulation of p53 expression, Survivin attenuates the suppressing effect of p53 on NF-κB(p50) expression and then enhances BCRP expression. This may represent a novel strategy for reversal of BCRP drug transporter activity to modulate MDR in cancer cells.
authors.affiliation: Department of Clinical Laboratory, The Shaoxing Hospital of China Medical University, Shaoxing, Zhejiang 312030, PR China.
authors.forename: Qing-ping
authors.initials: QP
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Xue-dong
authors.initials: XD
authors.lastname: Wang
authors.forename: Xi-ming
authors.initials: XM
authors.lastname: Mo
authors.forename: Juan
authors.initials: J
authors.lastname: Gu
authors.forename: Zhi-yong
authors.initials: ZY
authors.lastname: Lu
authors.forename: Zhao-lin
authors.initials: ZL
authors.lastname: Pan
authors.forename: Yu-xi
authors.initials: YX
authors.lastname: Zhu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D052002:NF-kappa B p50 Subunit / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D000077022:Survivin; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D052002:NF-kappa B p50 Subunit; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005472:Fluorouracil
keywords: 5-FU; 5-fluorouracil; BCRP; Breast cancer resistance protein; MDR; MX; Multidrug resistance; NF-κB; Survivin; breast cancer resistance protein; mitoxantrone; multidrug resistance; p53