The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells

Molecules. 2016 Mar 1;21(3):290. doi: 10.3390/molecules21030290.


Multidrug resistance (MDR) is often attributed to the over-expression of P-glycoprotein (P-gp), which prevents the accumulation of anticancer drugs within cells by virtue of its active drug efflux capacity. We have previously described the intercellular transfer of P-gp via extracellular vesicles (EVs) and proposed the involvement of a unique protein complex in regulating this process. In this paper, we investigate the role of these mediators in the regulation of P-gp functionality and hence the acquisition of MDR following cell to cell transfer. By sequentially silencing the FERM domain-binding proteins, Ezrin, Radixin and Moesin (ERM), as well as CD44, which we also report a selective packaging in breast cancer derived EVs, we have established a role for these proteins, in particular Radixin and CD44, in influencing the P-gp-mediated MDR in whole cells. We also report for the first time the role of ERM proteins in the vesicular transfer of functional P-gp. Specifically, we demonstrate that intercellular membrane insertion is dependent on Ezrin and Moesin, whilst P-gp functionality is governed by the integrity of all ERM proteins in the recipient cell. This study identifies these candidate proteins as potential new therapeutic targets in circumventing MDR clinically.

Keywords: CD44; Ezrin-Radixin-Moesin; P-glycoprotein; extracellular vesicles; multidrug resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cytoskeletal Proteins / metabolism
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Hyaluronan Receptors / metabolism
  • MCF-7 Cells
  • Membrane Proteins / metabolism
  • Microfilament Proteins / metabolism
  • Proteomics / methods
  • Transport Vesicles / metabolism


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • CD44 protein, human
  • Cytoskeletal Proteins
  • Hyaluronan Receptors
  • Membrane Proteins
  • Microfilament Proteins
  • ezrin
  • moesin
  • radixin