title: The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells.
abstract: 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.
authors.affiliation: Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney, Sydney NSW 2007, Australia. deep.pokharel@student.uts.edu.au.
authors.forename: Deep
authors.initials: D
authors.lastname: Pokharel
authors.affiliation: Proteomics Core Facility, University of Technology Sydney, Sydney NSW 2007, Australia. matthew.padula@uts.edu.au.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Padula
authors.affiliation: Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney, Sydney NSW 2007, Australia. Jamie.f.lu@student.uts.edu.au.
authors.forename: Jamie F
authors.initials: JF
authors.lastname: Lu
authors.affiliation: Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney, Sydney NSW 2007, Australia. ritu.jaiswal@uts.edu.au.
authors.forename: Ritu
authors.initials: R
authors.lastname: Jaiswal
authors.affiliation: Proteomics Core Facility, University of Technology Sydney, Sydney NSW 2007, Australia. steven.djordjevic@uts.edu.au.|The ithree Institute, University of Technology Sydney, Sydney NSW 2007, Australia. steven.djordjevic@uts.edu.au.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Djordjevic
authors.affiliation: Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney, Sydney NSW 2007, Australia. mary.bebawy@uts.edu.au.
authors.forename: Mary
authors.initials: M
authors.lastname: Bebawy
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D022161:Transport Vesicles / Q000378:metabolism; D000099149:Ezrin
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D003598:Cytoskeletal Proteins; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D008840:Microfilament Proteins; D000099149:Ezrin; C513055:ABCB1 protein, human; C497483:CD44 protein, human; C071058:moesin; C071776:radixin
keywords: CD44; Ezrin-Radixin-Moesin; P-glycoprotein; extracellular vesicles; multidrug resistance