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.
Highlights
Acute T lymphoblastic leukemia (T-ALL) is a hematologic malignancy occurring mostly in children with poor prognosis [1,2]
We previously reported that CCL25 selectively enhanced the resistance of MOLT4 and other T-ALL cells to TNF-a-mediated apoptosis [17]
When the cells were pretreated with an anti-CCR9 Ab prior to CCL25 stimulation, the co-distribution patterns of P-gp, p-ERM and F-actin were disrupted. These results suggested that CCL25-induced drug resistance in MOLT4 cells may involve a redistribution of P-gp on the plasma membrane and colocalization of P-gp with p-ERM protein and F-actin
Summary
Acute T lymphoblastic leukemia (T-ALL) is a hematologic malignancy occurring mostly in children with poor prognosis [1,2]. One of the major clinical obstacles in the treatment of hematologic malignancies is multidrug resistance (MDR). Classical MDR is the consequence of overexpression of transporter proteins, which belong to the family of ATP binding cassette (ABC) protein pumps and include P-glycoprotein (P-gp) and MDR related proteins. These proteins function to extrude the antitumor agents from the cytoplasm such that the multidrug resistant cells characteristically exhibit reduced levels of intracellular accumulation of drugs and show reduced cytotoxicity when compared with the parental cells [3]. It is reported that the expression and polarized distribution of P-gp are involved in its extrusion function [5,6]
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