Microparticles mediate MRP1 intercellular transfer and the re-templating of intrinsic resistance pathways

Abstract

Multidrug resistance (MDR) is a major impediment to the overall success of chemotherapy in clinical oncology. MDR has been primarily attributed by the ATP-dependent transmembrane proteins, P-glycoprotein (P-gp, ABCB1) and Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1). These proteins maintain sublethal concentrations of intracellular chemotherapeutics by virtue of their drug efflux capacity. In this study, we report the acquisition and dissemination of functional MRP1 via microparticle (MP) mediated intercellular transfer. After we showed the transfer and functionality of P-gp in drug sensitive recipient cells, we report the transfer and time-dependent functionality of MRP1 in drug sensitive leukaemia cells following exposure to MPs shed by MRP1-overexpressing MDR cells. We also demonstrate a remarkable capacity for MPs shed from cells with a P-gp dominant resistance profile to re-template a pre-existing MRP1 dominant profile in recipient cells. These findings have significance in understanding the molecular basis for tumour dominant phenotypes and introduce potential new strategies and targets for the acquisition of MDR and other deleterious traits.

Keywords: Ct; FCM; Intercellular transfer; MDR; MFI; MPs; MRP1; Microparticles; Multidrug Resistance-Associated Protein 1; Multidrug resistance; P-glycoprotein; P-gp; PBC; Re-templating; Trait dominance; a.u.; arbitrary units; cycle threshold; flow cytometry; mean fluorescence intensity; microparticles; multidrug resistance; probenecid; qRT-PCR; quantitative real-time PCR.