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.

Proteins Regulating Microvesicle Biogenesis and Multidrug Resistance in Cancer

“…They operate as signaling vectors in the intercellular transfer of functional P‐gp from drug‐resistant to drug‐sensitive cells . Furthermore, EVs consolidate the MDR phenotype by incorporating and transferring functional nucleic acids species and effectively ‘re‐template’ the transcriptional landscape of recipient cells . P‐gp containing EVs have also been shown to confer a parallel resistance pathway through a capacity for active drug sequestration .…”

“…[13,50,170,177] Furthermore, EVs consolidate the MDR phenotype by incorporating and transferring functional nucleic acids species and effectively 're-template' the transcriptional landscape of recipient cells. [170,177,178] P-gp containing EVs have also been shown to confer a parallel resistance pathway through a capacity for active drug sequestration. [49] Intriguingly, MV-mediated transfer of P-gp appears to be tissue selective-breast cancerderived MVs only transferred the MDR protein to malignant breast cells.…”

Cannabinoids, Blood–Brain Barrier, and Brain Disposition

“…Since several antipsychotic and anticonvulsants are considered substrates for P-glycoprotein (P-gp), it occurs that they are thrown out from the brain into the blood, which is an obstacle for brain accumulation [85]. ABC transporters have a key role in this kind of resistance [86]. They actively carry chemicals crossing biological membranes contributing to their disposal [87].…”

Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles

“…In addition to transferring P‐gp protein to recipient cells, many resistant lines can produce EVs carrying MDR1 (ABCB1) or MRP1 (ABCC1) mRNA which can be transferred into sensitive cells to induce resistance . A recent study highlighted the complexity of relationship between mRNAs and miRNAs delivered using leukemia cell line CCRF‐CEM and its multidrug resistant derivatives VLB 100 and E 1000 . The authors showed that ABCB1 (also known as MDR1 ), ABCC1 (also known as MRP1 ), and miR‐326 can all be delivered in EVs, but that expression of ABCB1 dominates while miR‐326 represses ABCC1.…”

“…[61,66,69,75,85] A recent study highlighted the complexity of relationship between mRNAs and miRNAs delivered using leukemia cell line CCRF-CEM and its multidrug resistant derivatives VLB 100 and E 1000 . [92] The authors showed that ABCB1 (also known as MDR1), ABCC1 (also known as MRP1), and miR-326 can all be delivered in EVs, but that expression of ABCB1 dominates while miR-326 represses ABCC1. If ABCB1 is knocked down then miR-326 represses ABCC1 less efficiently, suggesting a complex interplay between RNA delivered in EVs.…”