Drug resistance via radixin-mediated increase of P-glycoprotein membrane expression during SNAI1-induced epithelial-mesenchymal transition in HepG2 cells

Author:

Kamioka Hiroki1,Edaki Kazue2,Kasahara Haruka2,Tomono Takumi13,Yano Kentaro24,Ogihara Takuo12

Affiliation:

1. Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare, Takasaki-shi, Gunma, Japan

2. Laboratory of Biopharmaceutics, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki-shi, Gunma, Japan

3. Laboratory of Drug Delivery System, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata-shi, Osaka, Japan

4. Laboratory of Drug Metabolism and Pharmacokinetics, Yokohama University of Pharmacy, Yokohama, Kanagawa, Japan

Abstract

Abstract Objectives Epithelial–mesenchymal transition (EMT) plays a role in cancer metastasis as well as in drug resistance through various mechanisms, including increased drug efflux mediated by P-glycoprotein (P-gp). In this study, we investigated the activation mechanism of P-gp, including its regulatory factors, during EMT in hepatoblastoma-derived HepG2 cells. Methods HepG2 cells were transfected with SNAI1 using human adenovirus serotype 5 vector. We quantified mRNA and protein expression levels using qRT-PCR and western blot analysis, respectively. P-gp activity was evaluated by uptake assay, and cell viability was assessed by an MTT assay. Key findings P-gp protein expression on plasma membrane was higher in SNAI1-transfected cells than in Mock cells, although there was no difference in P-gp protein level in whole cells. Among the scaffold proteins such as ezrin, radixin and moesin (ERM), only radixin was increased in SNAI1-transfected cells. Uptake of both Rho123 and paclitaxel was decreased in SNAI1-transfected cells, and this decrease was blocked by verapamil, a P-gp inhibitor. The reduced susceptibility of SNAI1-transfected cells to paclitaxel was reversed by elacridar, another P-gp inhibitor. Conclusions Increased expression of radixin during SNAI1-induced EMT leads to increased P-gp membrane expression in HepG2 cells, enhancing P-gp function and thereby increasing drug resistance.

Funder

JSPS KAKENHI

Nagai Memorial Research Scholarship

Publisher

Oxford University Press (OUP)

Subject

Pharmaceutical Science,Pharmacology

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