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

Abstract

<p>P-glycoprotein (P-gp/<i>ABCB1</i>) and multidrug resistance-associated protein 1 (MRP1/<i>ABCC1</i>) 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 <i>ABCC1</i> by miR-326 is modulated by the presence of <i>ABCB1</i> transcript. Specifically, we show that siRNA silencing of MP-transferred <i>ABCB1</i> transcript reverses the knockdown effects of miRNA-326 on target MRP1/<i>ABCC1</i> transcripts. We also demonstrate a dominance of <i>ABCB1</i> transcripts when co-localized with <i>ABCC1</i> transcripts, which is consistent with the facilitation of miR-326 function by <i>ABCB1</i>. This study identifies a novel pathway regulating the expression of ABC transporters and positions <i>ABCB1</i> mRNA as a transcriptional regulator of other members of this superfamily in multidrug resistant cells through its actions on miRNAs.</p>