The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells
AbstractMultidrug 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. View Full-Text
- Supplementary File 1:
Supplementary (ZIP, 4727 KB)
Share & Cite This Article
Pokharel, D.; Padula, M.P.; Lu, J.F.; Jaiswal, R.; Djordjevic, S.P.; Bebawy, M. The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells. Molecules 2016, 21, 290.
Pokharel D, Padula MP, Lu JF, Jaiswal R, Djordjevic SP, Bebawy M. The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells. Molecules. 2016; 21(3):290.Chicago/Turabian Style
Pokharel, Deep; Padula, Matthew P.; Lu, Jamie F.; Jaiswal, Ritu; Djordjevic, Steven P.; Bebawy, Mary. 2016. "The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells." Molecules 21, no. 3: 290.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.