Drug resistance via radixin-mediated increase of P-glycoprotein membrane expression during SNAI1-induced epithelial-mesenchymal transition in HepG2 cells. (27th July 2021)

• Record Type: Journal Article
• Authors: Kamioka, Hiroki; Edaki, Kazue; Kasahara, Haruka; Tomono, Takumi; Yano, Kentaro; Ogihara, Takuo
• Is Part Of: Journal of pharmacy and pharmacology. Volume 73:Number 12(2021)
• Page Start: 1609
• Page End: 1616
• Publication Date: 2021-07-27
• Subjects: P-glycoprotein (P-gp) -- drug resistance -- cancer -- epithelial–mesenchymal transition (EMT) -- SNAI1 -- ezrin/radixin/moesin (ERM); Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1093/jpp/rgab051
• Languages: English
• ISSNs: 0022-3573

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.