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1. Biochem Pharmacol. 2012 Feb 8. [Epub ahead of print]

Inhibition of the PI3K-Akt signaling pathway disrupts ABCG2-rich extracellular
vesicles and overcomes multidrug resistance in breast cancer cells.

Goler-Baron V, Sladkevich I, Assaraf YG.

The Fred Wyszkowski Cancer Research Laboratory, Department of Biology,
Technion-Israel Institute of Technology, Haifa 32000, Israel.

We have recently shown that ABCG2-rich extracellular vesicles (EVs) form between
neighbor breast cancer cells and actively concentrate various chemotherapeutics,
resulting in multidrug resistance (MDR). Here we studied the signaling pathway
regulating ABCG2 targeting to EVs as its inhibition would overcome MDR. The
PI3K-Akt signaling pathway was possibly implicated in subcellular localization of
ABCG2; we accordingly show here that pharmacological inhibition of Akt signaling
results in gradual re-localization of ABCG2 from the EVs membrane to the
cytoplasm. Cytoskeletal markers including β-actin and the tight junction protein
ZO-1, along with the EVs markers ABCG2 and Ezrin-Radixin-Moesin revealed that
this intracellular ABCG2 retention leads to gradual decrease in the size and
number of EVs, resulting in EVs elimination and complete reversal of MDR.
Inhibition of Akt signaling restored drug sensitivity to mitoxantrone and
topotecan, bona fide ABCG2 transport substrates, hence being equivalent to MDR
reversal achieved with the ABCG2 transport inhibitor Ko143. Remarkably, apart
from loss of ABCG2 transport activity, treatment of MCF-7/MR cells with Ko143
resulted in cytoplasmic re-localization of ABCG2, similarly to the phenotype
observed after Akt inhibition. We conclude that the PI3K-Akt signaling pathway is
a key regulator of subcellular localization of ABCG2, EVs biogenesis and
functional MDR. Furthermore, proper folding of ABCG2 and its targeting to the EVs
membrane are crucial components of the biogenesis of EVs and their MDR function.
We propose that Akt signaling inhibitors which disrupt ABCG2 targeting and EVs
biogenesis may readily overcome MDR thus warranting in vivo studies with these
promising drug combinations.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID: 22342288 [PubMed - as supplied by publisher]