Snail-Induced Epithelial-to-Mesenchymal Transition Enhances P-gp-Mediated Multidrug Resistance in HCC827 Cells

Overexpression and activation of P-glycoprotein (P-gp), which mediates efflux transport of various anticancer drugs in cancer cells, is associated with multidrug resistance (MDR). On the other hand, malignant cancer cells frequently undergo epithelial-to-mesenchymal transition (EMT), thereby acquiri...

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Veröffentlicht in:Journal of pharmaceutical sciences 2017-09, Vol.106 (9), p.2642-2649
Hauptverfasser: Tomono, Takumi, Yano, Kentaro, Ogihara, Takuo
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Sprache:eng
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Zusammenfassung:Overexpression and activation of P-glycoprotein (P-gp), which mediates efflux transport of various anticancer drugs in cancer cells, is associated with multidrug resistance (MDR). On the other hand, malignant cancer cells frequently undergo epithelial-to-mesenchymal transition (EMT), thereby acquiring high migratory mobility and invasive ability. Snail is a transcriptional factor that represses multiple other factors, and its overexpression is a trigger of EMT. Because both P-gp and Snail are involved in malignant evolution of cancer, in this work, we evaluated whether EMT induced by overexpression of Snail influences P-gp expression and activity. Snail-overexpressing cells showed downregulation of epithelial markers, E-cadherin, occludin, and claudin-1, and upregulation of mesenchymal markers, vimentin and ZEB1. Although Western blot analysis showed that P-gp expression levels were similar in Mock and Snail-overexpressing cells, the results of P-gp functional assays with P-gp substrates rhodamine123 and paclitaxel indicated that P-gp is activated in Snail-overexpressing cells. Indeed, Snail-overexpressing cells showed greater viability than Mock cells in the presence of paclitaxel. We observed caveolin-1 dephosphorylation and decreased growth factor receptor-bound protein 2 (GRB2) expression in Snail-overexpressing cells. These findings suggest a novel pathway leading to cancer MDR, in which Snail induces EMT concomitantly with a decrease in GRB2-mediated caveolin-1 phosphorylation, resulting in activation of P-gp.
ISSN:0022-3549
1520-6017
DOI:10.1016/j.xphs.2017.03.011