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

Biochemical Pharmacology
Vicky Goler-BaronYehuda G Assaraf

Abstract

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 phenotyp...Continue Reading

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