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

Abstract

Simple SummaryMultidrug resistance and infiltration/metastasis of cancer are two major issues that must be overcome during chemotherapy. Efflux transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated proteins, and breast cancer resistance protein play an important role in multidrug resistance of cancer. The ERM scaffold protein ezrin, radixin, and moesin acts as an anchor to support the expression of these transporters on the cell membrane. This review summarizes the organ-specific relationship between efflux transporters and ERM proteins. Furthermore, we also describe how transcriptional regulatory factors such as Snail that play an active role in cancer metastasis, are involved in the activation of P-gp through the expression of ERM proteins. We hope that this review will be useful to many researchers in understanding how to overcome multidrug resistance in cancer.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.