Different Ability of Multidrug-Resistant and -Sensitive Counterpart Cells to Release and Capture Extracellular Vesicles.

Diana Sousa,M Helena Vasconcelos,Félix Royo,Juan M Falcón-Pérez,Raquel T Lima,Cristina P R Xavier,Vanessa Lopes-Rodrigues,Esperanza Gonzalez

doi:10.3390/cells10112886

Abstract

Cancer multidrug resistance (MDR) is one of the main challenges for cancer treatment efficacy. MDR is a phenomenon by which tumor cells become resistant to several unrelated drugs. Some studies have previously described the important role of extracellular vesicles (EVs) in the dissemination of a MDR phenotype. EVs’ cargo may include different players of MDR, such as microRNAS and drug-efflux pumps, which may be transferred from donor MDR cells to recipient drug-sensitive counterparts. The present work aimed to: (i) compare the ability of drug-sensitive and their MDR counterpart cells to release and capture EVs and (ii) study and relate those differences with possible distinct fate of the endocytic pathway in these counterpart cells. Our results showed that MDR cells released more EVs than their drug-sensitive counterparts and also that the drug-sensitive cells captured more EVs than their MDR counterparts. This difference in the release and capture of EVs may be associated with differences in the endocytic pathway between drug-sensitive and MDR cells. Importantly, manipulation of the recycling pathway influenced the response of drug-sensitive cells to doxorubicin treatment.

Highlights

Drug resistance is a major impediment for cancer treatment success [1]
We found that Multidrug resistance (MDR) cells produced larger extracellular vesicles (EVs) than their drug-sensitive counterparts
EVs from MDR cells contained P-gp and presented a different content of proteins known to be involved in the biogenesis of EVs [22]

Summary

Introduction

Multidrug resistance (MDR) occurs in cells which become resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered [2]. Several mechanisms, such as increase in drug efflux, inhibition of apoptosis, alterations in cell cycle profile, or decrease in drug influx, may be responsible for the MDR phenotype [3]. The documented intercellular transfer of the drug-efflux pump P-glycoprotein (P-gp), mediated by extracellular vesicles (EVs) released by MDR cells and the subsequent acquisition of a MDR phenotype by the recipient sensitive tumor cells, was an important finding in this field of research [4]. The horizontal transfer of MDR phenotype to drug-sensitive cells has been evidenced by several of them [11,12,13]

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Conclusion