Activated ERM protein plays a critical role in drug resistance of MOLT4 cells induced by CCL25

Li Zhang; Ruijing Xiao; Jie Xiong; Jun Leng; Altaf Ehtisham; Yi Hu; Qianshan Ding; Hui Xu; Shengwu Liu; Jin Wang; Dean G Tang; Qiuping Zhang

doi:10.1371/journal.pone.0052384

Activated ERM protein plays a critical role in drug resistance of MOLT4 cells induced by CCL25

PLoS One. 2013;8(1):e52384. doi: 10.1371/journal.pone.0052384. Epub 2013 Jan 9.

Authors

Li Zhang¹, Ruijing Xiao, Jie Xiong, Jun Leng, Altaf Ehtisham, Yi Hu, Qianshan Ding, Hui Xu, Shengwu Liu, Jin Wang, Dean G Tang, Qiuping Zhang

Affiliation

¹ Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, China.

Abstract

We have previously demonstrated that the CCR9/CCL25 signaling pathway plays an important role in drug resistance in human acute T-lymphocytic leukemia (T-ALL) by inducing activation of ERM protein with polarized distribution in T-ALL cell line MOLT4. However, the mechanism of action of the activated ERM protein in the drug resistance of MOLT4 cells induced by CCL25 remains uncharacterized. Here we investigated the mechanism of CCR9/CCL25-initiated drug resistance in CCR9-high-expressing T-ALL cells. Our results showed that 1) the function of P-gp was increased after treatment with CCL25; 2) P-gp colocalized and co-immunoprecipitated with p-ERM and F-actin in CCL25 treated cells; and 3) ERM-shRNA conferred drug sensitivity coincident with release of ERM interactions with P-gp and F-actin after treatment with CCL25. These data suggest it is pivotal that P-gp associate with the F-actin cytoskeleton through p-ERM in CCR9/CCL25 induced multidrug resistance of T-ALL cells. Strategies aimed at inhibiting P-gp-F-actin cytoskeleton association may be helpful in increasing the efficiency of therapies in T-ALL.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Actins / metabolism
Antibiotics, Antineoplastic / pharmacology
Apoptosis / drug effects
Apoptosis / genetics
Blotting, Western
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Chemokines, CC / pharmacology*
Cytoskeletal Proteins / genetics*
Cytoskeletal Proteins / metabolism
Doxorubicin / pharmacology
Drug Resistance, Multiple / drug effects
Drug Resistance, Multiple / genetics
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
Flow Cytometry
Gene Expression Regulation, Leukemic
Humans
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Microfilament Proteins / genetics*
Microfilament Proteins / metabolism
Microscopy, Confocal
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
Protein Binding
RNA Interference
Receptors, CCR / metabolism
Reverse Transcriptase Polymerase Chain Reaction

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Actins
Antibiotics, Antineoplastic
CC chemokine receptor 9
CCL25 protein, human
Chemokines, CC
Cytoskeletal Proteins
Membrane Proteins
Microfilament Proteins
Receptors, CCR
ezrin
moesin
radixin
Doxorubicin

Grants and funding

This work was supported by National Science Foundation of China (No.30570780, 30971280, 30801336), National Ministry of Doctoral Fund (No.200804860039) and the Fundamental Research Funds for the Central Universities (No.301274622). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.