Moesin-Mediated P-Glycoprotein Activation During Snail-Induced Epithelial-Mesenchymal Transition in Lung Cancer Cells

Kamioka, Hiroki; Tomono, Takumi; Fujita, Atsushi; Onozato, Ryoichi; Iijima, Misa; Tsuchida, Shigeru; Arai, Takahiro; Fujita, Yukiyoshi; Zhang, Xieyi; Yano, Kentarô; Ogihara, Takuo

doi:10.1016/j.xphs.2020.03.008

Cited by 15 publications

(16 citation statements)

References 38 publications

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“…We also examined clinical samples collected from lung cancer patients [101], and surprisingly found that the mRNA expression level of Snail was positively correlated not only with Msn, but also with Rdx and Ezr, as well as with P-gp mRNA. In other words, Snail appears to be indirectly involved in the increase of P-gp activity in lung cancer by stimulating the expression of Msn, according to in vitro studies.…”

Section: Change Of P-gp Activity Associated With Emtmentioning

confidence: 99%

“…Thus, it is possible that Snail is involved in the expression and activity of P-gp. We investigated the involvement of ERM proteins in P-gp activation during Snail-induced EMT in lung cancer cells [100,101]. The mRNA expression levels of epithelial markers such as E-cadherin, occludin, and claudin-1 were reduced in Snail-overexpressing cells, whereas these of mesenchymal markers such as vimentin and ZEB1 were increased in Snail-overexpressing cells compared with Mock cells.…”

Section: Change Of P-gp Activity Associated With Emtmentioning

confidence: 99%

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Physiological Roles of ERM Proteins and Transcriptional Regulators in Supporting Membrane Expression of Efflux Transporters as Factors of Drug Resistance in Cancer

Ogihara

Mizoi

Kamioka

et al. 2020

Cancers

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One factor contributing to the malignancy of cancer cells is the acquisition of drug resistance during chemotherapy via increased expression of efflux transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP). These transporters operate at the cell membrane, and are anchored in place by the scaffold proteins ezrin (Ezr), radixin (Rdx), and moesin (Msn) (ERM proteins), which regulate their functional activity. The identity of the regulatory scaffold protein(s) differs depending upon the transporter, and also upon the tissue in which it is expressed, even for the same transporter. Another factor contributing to malignancy is metastatic ability. Epithelial–mesenchymal transition (EMT) is the first step in the conversion of primary epithelial cells into mesenchymal cells that can be transported to other organs via the blood. The SNAI family, a transcriptional regulators triggers EMT, and SNAI expression is used is an indicator of malignancy. Furthermore, EMT has been suggested to be involved in drug resistance, since drug excretion from cancer cells is promoted during EMT. We showed recently that ERM proteins are induced by a member of the SNAI family, Snail. Here, we first review recent progress in research on the relationship between efflux transporters and scaffold proteins, including the question of tissue specificity. In the second part, we review the relationship between ERM scaffold proteins and the transcriptional regulatory factors that induce their expression.

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Section: Change Of P-gp Activity Associated With Emtmentioning

confidence: 99%

Section: Change Of P-gp Activity Associated With Emtmentioning

confidence: 99%

Physiological Roles of ERM Proteins and Transcriptional Regulators in Supporting Membrane Expression of Efflux Transporters as Factors of Drug Resistance in Cancer

Ogihara

Mizoi

Kamioka

et al. 2020

Cancers

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“…The intracellular accumulation of Rho123 was determined as described previously with some modifications [22,23,[31][32][33][34]. After treatment with siRNAs for 3 days, the LS180 cells were pretreated with 50 μM of verapamil (FUJIFILM Wako Pure Chemical), a classical inhibitor of the P-gp function [35], for 30 min followed by incubation with 50 μM of Rho123 (Merck) as a P-gp substrate in the dark for 2 h at 37˚C in a humidified atmosphere with 5% CO 2 .…”

Section: Rho123 Accumulation Studymentioning

confidence: 99%

Subcellular distribution of ezrin/radixin/moesin and their roles in the cell surface localization and transport function of P-glycoprotein in human colon adenocarcinoma LS180 cells

et al. 2021

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The ezrin/radixin/moesin (ERM) family proteins act as linkers between the actin cytoskeleton and P-glycoprotein (P-gp) and regulate the plasma membrane localization and functionality of the latter in various cancer cells. Notably, P-gp overexpression in the plasma membrane of cancer cells is a principal factor responsible for multidrug resistance and drug-induced mutagenesis. However, it remains unknown whether the ERM proteins contribute to the plasma membrane localization and transport function of P-gp in human colorectal cancer cells in which the subcellular localization of ERM has yet to be determined. This study aimed to determine the gene expression patterns and subcellular localization of ERM and P-gp and investigate the role of ERM proteins in the plasma membrane localization and transport function of P-gp using the human colon adenocarcinoma cell line LS180. Using real-time reverse transcription polymerase chain reaction and immunofluorescence analyses, we showed higher levels of ezrin and moesin mRNAs than those of radixin mRNA in these cells and preferential distribution of all three ERM proteins on the plasma membrane. The ERM proteins were highly colocalized with P-gp. Additionally, we show that the knockdown of ezrin, but not of radixin and moesin, by RNA interference significantly decreased the cell surface expression of P-gp in LS180 cells without affecting the mRNA expression of P-gp. Furthermore, gene silencing of ezrin substantially increased the intracellular accumulation of rhodamine123, a typical P-gp substrate, with no alterations in the plasma membrane permeability of Evans blue, a passive transport marker. In conclusion, ezrin may primarily regulate the cell surface localization and transport function of P-gp as a scaffold protein without influencing the transcriptional activity of P-gp in LS180 cells. These findings should be relevant for treating colorectal cancer, which is the second leading cause of cancer-related deaths in males and females combined.

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“…In particular, we recently reported that BCRP and P-gp transport functions in HCC827 cells are regulated by ezrin and moesin. 44,45) Moreover, we showed that the function of P-gp is enhanced without any increase in its mRNA level in HCC827 cells with Snail-induced EMT. 12,13) Furthermore, Snail-induced increase in moesin expression was involved in the mechanism of P-gp hyperactivity.…”

Section: Discussionmentioning

confidence: 80%

Functional Alterations of Multidrug Resistance-Associated Proteins 2 and 5, and Breast Cancer Resistance Protein upon Snail-Induced Epithelial–Mesenchymal Transition in HCC827 Cells

Yano

Todokoro

Kamioka

et al. 2021

Biological & Pharmaceutical Bulletin

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Moesin-Mediated P-Glycoprotein Activation During Snail-Induced Epithelial-Mesenchymal Transition in Lung Cancer Cells

Cited by 15 publications

References 38 publications

Physiological Roles of ERM Proteins and Transcriptional Regulators in Supporting Membrane Expression of Efflux Transporters as Factors of Drug Resistance in Cancer

Physiological Roles of ERM Proteins and Transcriptional Regulators in Supporting Membrane Expression of Efflux Transporters as Factors of Drug Resistance in Cancer

Subcellular distribution of ezrin/radixin/moesin and their roles in the cell surface localization and transport function of P-glycoprotein in human colon adenocarcinoma LS180 cells

Functional Alterations of Multidrug Resistance-Associated Proteins 2 and 5, and Breast Cancer Resistance Protein upon Snail-Induced Epithelial–Mesenchymal Transition in HCC827 Cells

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