A novel mechanism governing the transcriptional regulation of ABC transporters in MDR cancer cells

Lu, JF; Pokharel, D; Bebawy, M

A novel mechanism governing the transcriptional regulation of ABC transporters in MDR cancer cells

Lu, JF Pokharel, D Bebawy, M

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Publication Type:: Journal Article
Citation:: Drug Delivery and Translational Research, 2017, 7 (2), pp. 276 - 285
Issue Date:: 2017-04-01

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Field	Value	Language
dc.contributor.author	Lu, JF	en_US
dc.contributor.author	Pokharel, D	en_US
dc.contributor.author	Bebawy, M https://orcid.org/0000-0003-2606-921X	en_US
dc.date.issued	2017-04-01	en_US
dc.identifier.citation	Drug Delivery and Translational Research, 2017, 7 (2), pp. 276 - 285	en_US
dc.identifier.issn	2190-393X	en_US
dc.identifier.uri	http://hdl.handle.net/10453/110577
dc.description.abstract	© 2016, Controlled Release Society. 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.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1007613
dc.relation.ispartof	Drug Delivery and Translational Research	en_US
dc.relation.isbasedon	10.1007/s13346-016-0353-4	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Multidrug Resistance-Associated Proteins	en_US
dc.subject.mesh	ATP Binding Cassette Transporter, Sub-Family B	en_US
dc.subject.mesh	ATP Binding Cassette Transporter, Subfamily B	en_US
dc.subject.mesh	Cell-Derived Microparticles	en_US
dc.subject.mesh	Drug Resistance, Multiple	en_US
dc.subject.mesh	Drug Resistance, Neoplasm	en_US
dc.subject.mesh	Gene Expression Regulation, Neoplastic	en_US
dc.subject.mesh	MicroRNAs	en_US
dc.subject.mesh	RNA, Small Interfering	en_US
dc.title	A novel mechanism governing the transcriptional regulation of ABC transporters in MDR cancer cells	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	7	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Graduate School of Health
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	7	en_US

Abstract:

© 2016, Controlled Release Society. 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.

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http://hdl.handle.net/10453/110577