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Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK
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Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK
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Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK
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Journal Article
Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK
2017
Overview
Background:
Chemoresistance is a significant clinical problem in pancreatic cancer (PC) and underlying molecular mechanisms still remain to be completely understood. Here we report a novel exosome-mediated mechanism of drug-induced acquired chemoresistance in PC cells.
Methods:
Differential ultracentrifugation was performed to isolate extracellular vesicles (EVs) based on their size from vehicle- or gemcitabine-treated PC cells. Extracellular vesicles size and subtypes were determined by dynamic light scattering and marker profiling, respectively. Gene expression was examined by qRT-PCR and/or immunoblot analyses, and direct targeting of DCK by miR-155 was confirmed by dual-luciferase 3′-UTR reporter assay. Flow cytometry was performed to examine the apoptosis indices and reactive oxygen species (ROS) levels in PC cells using specific dyes. Cell viability was determined using the WST-1 assay.
Results:
Conditioned media (CM) from gemcitabine-treated PC cells (Gem-CM) provided significant chemoprotection to subsequent gemcitabine toxicity and most of the chemoresistance conferred by Gem-CM resulted from its EVs fraction. Sub-fractionation grouped EVs into distinct subtypes based on size distribution and marker profiles, and exosome (Gem-Exo) was the only sub-fraction that imparted chemoresistance. Gene expression analyses demonstrated upregulation of
SOD2
and
CAT
(ROS-detoxifying genes), and downregulation of
DCK
(gemcitabine-metabolising gene) in Gem-Exo-treated cells.
SOD/CAT
upregulation resulted, at least in part, from exosome-mediated transfer of their transcripts and they suppressed basal and gemcitabine-induced ROS production, and partly promoted chemoresistance.
DCK
downregulation occurred through exosome-delivered miR-155 and either the functional suppression of miR-155 or restoration of
DCK
led to marked abrogation of Gem-Exo-mediated chemoresistance.
Conclusions:
Together, these findings establish a novel role of exosomes in mediating the acquired chemoresistance of PC.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Biomedical and Life Sciences
/ Deoxycytidine - analogs & derivatives
/ Deoxycytidine - pharmacology
/ Deoxycytidine Kinase - genetics
/ Gene Expression Regulation, Neoplastic - drug effects
/ Humans
/ Oncology
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - metabolism
/ Reactive Oxygen Species - metabolism
