title: A novel mechanism governing the transcriptional regulation of ABC transporters in MDR cancer cells.
abstract: P-glycoprotein (P-gp/ABCB1) and multidrug resistance-associated protein 1 (MRP1/ABCC1) are the main drug efflux transporters associated with treatment failure in cancer. Much attention has been focused on the molecular mechanisms regulating the expression of these transporters as a viable approach for identifying novel drug targets in circumventing cancer multidrug resistance (MDR) clinically. In this paper, we examine the role of miR-326 in the context of its intercellular transfer between cancer cells by extracellular membrane vesicles called microparticles (MPs). We observe that cellular suppression of ABCC1 by miR-326 is modulated by the presence of ABCB1 transcript. Specifically, we show that siRNA silencing of MP-transferred ABCB1 transcript reverses the knockdown effects of miRNA-326 on target MRP1/ABCC1 transcripts. We also demonstrate a dominance of ABCB1 transcripts when co-localized with ABCC1 transcripts, which is consistent with the facilitation of miR-326 function by ABCB1. This study identifies a novel pathway regulating the expression of ABC transporters and positions ABCB1 mRNA as a transcriptional regulator of other members of this superfamily in multidrug resistant cells through its actions on miRNAs.
authors.affiliation: Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, Sydney, NSW, 2007, Australia.
authors.forename: Jamie F
authors.initials: JF
authors.lastname: Lu
authors.affiliation: Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, Sydney, NSW, 2007, Australia.
authors.forename: Deep
authors.initials: D
authors.lastname: Pokharel
authors.affiliation: Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, Sydney, NSW, 2007, Australia. mary.bebawy@uts.edu.au.
authors.forename: Mary
authors.initials: M
authors.lastname: Bebawy
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D035683:MicroRNAs; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D034741:RNA, Small Interfering; C513055:ABCB1 protein, human; C545322:MIRN326 microRNA, human; C421109:multidrug resistance-associated protein 1
keywords: Cancer; Extracellular vesicles; Microparticles; Multidrug resistance; P-glycoprotein; miR-326