Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For children with acute myeloblastic leukemia (AML), multidrug resistance (MDR) reduces treatment effectiveness, and often leads to poor patient survival. While a number of factors have been described that affect MDR, the mechanisms underlying this effect remain unclear. In this study, the role of WAVE1 in MDR was investigated. Among 62 children with AML, high levels of WAVE1 were associated with poor patient outcomes. Proteomic techniques were used to identify novel WAVE1-interacting proteins from leukemia cells, one of which was the cytoskeleton regulator Ezrin. In leukemia cells, WAVE1 co-localized with both Ezrin and P-glycoprotein (P-gp), a critical regulator of the MDR phenotype. Overexpression of WAVE1 in K562 leukemia cells up-regulated P-gp and Ezrin, and reduced K562 cells' sensitivity to the chemotherapy drug adriamycin. The opposite effect was seen when WAVE1 expression was reduced via RNA interference. Critically, overexpression of WAVE1 in the absence of Ezrin did not affect P-gp levels or MDR. These data suggest that WAVE1 affects P-gp and MDR of leukemia cells through Ezrin.
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PMID:WAVE1 regulates P-glycoprotein expression via Ezrin in leukemia cells. 2128 Dec 39

Overexpression of the mdr1 gene encoding P-glycoprotein (Pgp) exerts a major role in reducing the effectiveness of cytotoxic therapy in osteosarcoma. The interaction between actin and Pgp has been shown to be instrumental in the establishment of multidrug resistance (MDR) in human tumor cells. The cytoskeleton linker ezrin exerts a pivotal role in maintaining the functional connection between actin and Pgp. We investigated the role of ezrin in a human multidrug-resistant osteosarcoma cell line overexpressing Pgp and compared it to its counterpart that overexpresses an ezrin deletion mutant. The results showed that Pgp binds at amino acid residues 149-242 of the N-terminal domain of ezrin. The interaction between ezrin and Pgp occurs in the plasma membrane of MDR cells, where they also co-localize with the ganglioside G(M1) located in lipid rafts. The overexpression of the ezrin deletion mutant entirely restored drug susceptibility of osteosarcoma cells, consistent with Pgp dislocation to cytoplasmic compartments and abrogation of G(M1) /Pgp co-localization at the plasma membrane. Our study provides evidence that ezrin exerts a key role in MDR of human osteosarcoma cells through a Pgp-ezrin-actin connection that is instrumental for the permanence of Pgp into plasma membrane lipid rafts. We also show for the first time that Pgp-binding site is localized to amino acid residues 149-242 of the ezrin Band 4.1, Ezrin/Radixin/Moesin (FERM) domain, thus proposing a specific target for future molecular therapy aimed at counteracting MDR in osteosarcoma patients.
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PMID:P-glycoprotein binds to ezrin at amino acid residues 149-242 in the FERM domain and plays a key role in the multidrug resistance of human osteosarcoma. 2178 Jan 1

Ezrin, radixin, and moesin (ERM) proteins regulate functional expression of certain transporters, but little is known about their effect on P-glycoprotein (P-gp). Here, we investigated the influence of ERM proteins on the expression and activity of P-gp at the transcriptional, translational, and posttranslational levels, using HepG2 as a model cell line. Knockdown of ezrin with RNA interference decreased the level of P-gp messenger RNA. On the contrary, knockdown of radixin caused a decrease of the P-gp gene product at the cell surface, but not in whole cell lysate. Furthermore, a significant increase in accumulation of rhodamine123, a typical P-gp substrate, was observed in radixin knockdown cells, compared with control cells. Knockdown of moesin did not influence the expression or function of P-gp. These results indicate that ezrin influences the expression of P-gp at the translational level, whereas radixin is involved in membrane localization of P-gp in HepG2 cells.
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PMID:Effect of knockdown of ezrin, radixin, and moesin on P-glycoprotein function in HepG2 cells. 2183 48

Microparticles (MPs) play a vital role in cell communication by facilitating the horizontal transfer of cargo between cells. Recently, we described a novel "non-genetic" mechanism for the acquisition of multidrug resistance (MDR) in cancer cells by intercellular transfer of functional P-gp, via MPs. MDR is caused by the overexpression of the efflux transporters P-glycoprotein (P-gp) and Multidrug Resistance-Associated Protein 1 (MRP1). These transporters efflux anticancer drugs from resistant cancer cells and maintain sublethal intracellular drug concentrations. By conducting MP transfer experiments, we show that MPs derived from DX breast cancer cells selectively transfer P-gp to malignant MCF-7 breast cells only, in contrast to VLB100 leukaemic cell-derived MPs that transfer P-gp and MRP1 to both malignant and non-malignant cells. The observed transfer selectivity is not the result of membrane restrictions for intercellular exchange, limitations in MP binding to recipient cells or the differential expression of the cytoskeletal protein, Ezrin. CD44 (isoform 10) was found to be selectively present on the breast cancer-derived MPs and not on leukaemic MPs and may contribute to the observed selective transfer of P-gp to malignant breast cells observed. Using the MCF-7 murine tumour xenograft model we demonstrated the stable transfer of P-gp by MPs in vivo, which was found to localize to the tumour core as early as 24 hours post MP exposure and to remain stable for at least 2 weeks. These findings demonstrate a remarkable capacity by MPs to disseminate a stable resistant trait in the absence of any selective pressure.
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PMID:Breast cancer-derived microparticles display tissue selectivity in the transfer of resistance proteins to cells. 2359 86

Altered expression of P-glycoprotein (P-gp), a drug efflux transporter expressed by brain capillary endothelial cells (BCECs), may contribute to the development of opioid analgesic tolerance, as demonstrated by cumulative evidence from research. However, the detailed mechanism by which chronic morphine treatment increases P-gp expression remains unexplained. Ezrin/radixin/moesin (ERM) are scaffold proteins that are known to regulate the plasma membrane localization of some drug transporters such as P-gp in peripheral tissues, although a few reports suggest its role in the central nervous system as well. In this study, we investigated the involvement of ERM in the development of morphine analgesic tolerance through altered P-gp expression in BCECs. Repeated treatment with morphine (10 mg/kg/day, s.c. for 5 days) decreased its analgesic effect in the tail-flick test and increased P-gp protein expression in BCECs, as determined by Western blotting. Furthermore, moesin protein expression increased in the same fraction whereas that of ezrin decreased; no change was observed in the radixin expression. Furthermore, immunoprecipitation and immunofluorescence assays revealed interaction between moesin and P-gp molecules, along with co-localization, in BCECs. In conclusion, an increase in moesin expression may contribute to the increased expression of P-gp in BCECs, leading to the development of morphine analgesic tolerance.
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PMID:Involvement of moesin in the development of morphine analgesic tolerance through P-glycoprotein at the blood-brain barrier. 2504 10

Cancer multidrug resistance (MDR) occurs when cancer cells evade the cytotoxic actions of chemotherapeutics through the active efflux of drugs from within the cells. Our group have previously demonstrated that multidrug-resistant breast cancer cells spontaneously shed microparticles (MPs) and that these MPs can transfer resistance to drug-responsive cells and confer MDR on those cells in as little as 4 h. Furthermore, we also showed that, unlike MPs derived from leukaemia cells, breast cancer-derived MPs display a tissue selectivity in the transfer of P-glycoprotein (P-gp), transferring the resistance protein only to malignant breast cells. This study aims to define the proteome of breast cancer-derived MPs in order to understand the differences in protein profiles between those shed from drug-resistant versus drug-sensitive breast cancer cells. In doing so, we detail the protein cargo required for the intercellular transfer of MDR to drug-sensitive recipient cells and the factors governing the transfer selectivity to malignant breast cells. We describe the first proteomic analysis of MPs derived from human breast cancer cells using SDS PAGE and liquid chromatography-tandem mass spectrometry (LC/MS/MS), in which we identify 120 unique proteins found only in drug-resistant, breast cancer-derived MPs. Our results demonstrate that the MP-mediated transfer of P-gp to recipient cells occurs alongside CD44; the Ezrin, Radixin and Moesin protein family (ERM); and cytoskeleton motor proteins within the MP cargo.
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PMID:Proteome analysis of multidrug-resistant, breast cancer-derived microparticles. 2520 59

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.
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PMID:The Role of CD44 and ERM Proteins in Expression and Functionality of P-glycoprotein in Breast Cancer Cells. 2693 23

Chemokine ligand 25 (CCL25) and chemokine receptor 9 (CCR9) are important regulators of migration, proliferation and apoptosis in leukocytes and cancer cells. Blocking of the CCR9/CCL25 signal has been demonstrated to be a potential novel cancer therapy. Research into CCR9 and CCL25 has revealed their associated upstream and downstream signaling pathways; CCR9 is regulated by several immunological factors, including NOTCH, interleukin 2, interleukin 4 and retinoic acid. NOTCH in particular, has been revealed to be a crucial upstream regulator of CCR9. Furthermore, proteins including matrix metalloproteinases, P-glycoprotein, Ezrin/Radixin/Moesin and Livin are regulated via phosphatidylinositol-3 kinase/protein kinase B, which are in turn stimulated by CCR9/CCL25. This is a review of the current literature on the functions and signaling pathways of CCR9/CCL25.
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PMID:The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells. 3000 2