Mitochondrial localization and activity of P-glycoprotein in doxorubicin-resistant K562 cells

E, Munteanu; Verdier, Mireille; Grandjean‐Forestier, Fabienne; Stenger, Christophe; Jayat-Vignoles, Chantal; Huet, Sylvie; Robert, Jacques; Ratinaud, Marie‐Hélène

doi:10.1016/j.bcp.2006.01.006

Cited by 67 publications

(61 citation statements)

References 37 publications

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“…The mitochondrial localization of P-gp has been previously shown in human hepatocarcinoma, hepatoma, breast cancer and myeloid leukemia cell lines. [35][36][37][38] Mitochondria are the site where converge many of the factors, including members of Bcl-2 family, which elicit apoptosis. 39 This subcellular distribution suggests that P-gp may participate in the regulation of apoptosis presumably via the mitochondrial pathway.…”

Section: Discussionmentioning

confidence: 99%

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

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Liguori

et al. 2012

Laboratory Investigation

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P-glycoprotein (P-gp), traditionally linked to cancer poor prognosis and multidrug resistance, is undetectable in normal gastric mucosa and overexpressed in gastric cancer (GC). We propose that P-gp may be involved in Helicobacter pylori (Hp)-related gastric carcinogenesis by inhibiting apoptosis. Aim of the study was to evaluate the expression of P-gp in fetal stomach and in Hp-related gastric carcinogenesis, the epigenetic control of the multi-drug resistance-1 (MDR1) gene, the localization and interaction between P-gp and Bcl-x L and the effect of the selective silencing of P-gp on cell survival. P-gp and Bcl-xl expression was evaluated by immunohistochemistry on 28 spontaneously abortive human fetuses, 66 Hp-negative subjects, 138 Hp-positive chronic gastritis (CG) of whom 28 with intestinal metaplasia (IM) and 45 intestinal type GCs. P-gp/Bcl-x L colocalization was investigated by confocal immunofluorescence microscopy and protein-protein interaction by co-immunoprecipitation, in basal conditions and after stress-induced apoptosis, in GC cell lines AGS and MKN-28 and hepatocellular carcinoma cell line Hep-G2. The role of P-gp in controlling apoptosis was evaluated by knocking down its expression with a specific small interfering RNAs in stressed AGS and MKN-28 cell lines. P-gp is expressed in the gastric mucosa of all human fetuses while, it is undetectable in adult normal mucosa and re-expressed in 30/110 Hp-positive non-IM-CG, 28/28 IM-CG and 40/45 GCs. P-gp expression directly correlates with that of Bcl-x L and with the promoter hypomethylation of the MDR1 gene. In GC cell lines, P-gp is localized on the plasma membrane and mitochondria where it colocalizes with Bcl-x L . Co-immunoprecipitation confirms the physical interaction between P-gp and Bcl-x L in AGS, MKN-28 and Hep-G2, at both basal level and after stress-induced apoptosis. The selective silencing of P-gp sensitizes GC cells to stress-induced apoptosis. P-gp behaves as an oncofetal protein that, by cross-talking with Bcl-x L , acts as an anti-apoptotic agent in Hp-related gastric carcinogenesis.Laboratory Investigation (2012) 92, 1407-1418; doi:10.1038/labinvest.2012.100; published online 2 July 2012 KEYWORDS: apoptosis; gastric carcinogenesis; H. pylori; P-glycoprotein; stomach morphogenesis P-glycoprotein (P-gp), the main product of the multi-drug resistance-1 (MDR1) gene, is a membrane-associated glycoprotein, normally expressed on the apical membrane of various cell types, 1 where it extrudes drugs and other toxic agents by acting as an energy-dependent efflux pump. 2 P-gp has been related to the intrinsic and acquired drug resistance in several neoplasms and represents one of the leading cause of the failure of chemotherapeutic treatments and poor prognosis of cancer. 3,4 In the gastrointestinal tract, under physiological conditions, P-gp expression progressively decreases from ileum, where it shows the maximum level of expression, to the stomach where it is absent. 5 In contrast, P-gp is generally overexpressed in gastric cancer (GC), wh...

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Section: Discussionmentioning

confidence: 99%

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Rocco

Compare

Liguori

et al. 2012

Laboratory Investigation

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“…Furthermore, intracellular levels of P-gp are roughly equivalent to that of the plasma membrane P-gp. Like the plasma membrane P-gp, the cytoplamic localization of P-gp may play an important role in tumor resistance (5).…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondria also have a very close relationship with apoptosis and tumor drug resistance. Research has revealed that mitochondria might be the primary compartment for sequestration of antineoplastic drugs in MDR cells (5,6). However, studies are inconclusive as to whether or not the mitochondrial sequestration of drugs is associated with mitochondrial localization of P-gp and its functional properties (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial localization of P-glycoprotein in the human breast cancer cell line MCF-7/ADM and its functional characterization

et al. 2012

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Abstract. The current view of multidrug resisitance is that overexpression of membrane P-glycoprotein (P-gp) is a major causative factor. However, the controversial presence of subcellular P-gp may also participate in the drug resistance. In this study, we sought to investigate the localization and functional characterization of P-gp in mitochondria isolated from MCF-7 and doxorubicin-resistant MCF-7 (MCF-7/ ADM) cells. Mitochondria were isolated and purified from the MCF-7 cell line and its resistant cells MCF-7/ADM. We used electron microscopy, western blot analysis and confocal microscopy to demonstrate the localization of P-gp in the mitochondria of MCF-7/ADM cells. Flow cytometry was used to evaluated the efflux function of mitochondrial P-gp in the presence or absence of the P-gp inhibitor cyclosporine A (CsA). Mitochondria were isolated and purified successfully and were analyzed by electron microscopy. Western blotting demonstrated the expression of P-gp in the cell membrane and purified mitochondria from MCF-7/ADM cells but not from sensitive MCF-7 cells. Immunofluorescence analysis using confocal microscopy demonstrated the localization of P-gp [labeled with green fluorescence (FITC)] to the mitochondria [labeled with red fluorescence (Mitotracker Deep Red 633)] of MCF-7/ADM cells and that was absent in MCF-7 cells. Rho123 (a mitochondrial fluorescent probe) accumulation was largely reduced and efflux was strongly increased in the mitochondria of MCF-7/ADM cells compared to those of MCF-7 cells (P<0.01), and these were completely reversed in the presence of the P-gp inhibitor CsA (P<0.01). No significant changes were observed in the mitochondria of MCF-7 cells (P>0.05). P-gp is expressed in the mitochondria of doxorubicin-resistant MCF-7 cells and has an efflux function. It could be involved in multidrug resistance at the subcellular site by pumping out anticancer drugs from mitochondria to protect the function of mitochondria.

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“…In this regard, mitochondrial expression of P-gp may protect the mitochondrial DNA from damage caused by anticancer drugs, and may be involved in the blockage of cytochrome C release into the cytosol in MDR cells. However, Munteanu et al (18) showed that in a human myeloid leukemia cell line (parental-sensitive cells and doxorubicin-resistant cells) K562, P-gp worked in the opposite direction by increasing the influx of anticancer drugs into the mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Increased P-glycoprotein expression in mitochondria is related to acquired multidrug resistance in human hepatoma cells depleted of mitochondrial DNA

Ling

Zhang

et al. 2011

Int J Oncol

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Abstract. Mitochondrial DNA-depleted ρ 0 cells are resistant to apoptosis, but the mechanism remains unclear. A human hepatoma cell line (SK-Hep1) depleted of mtDNA (ρ 0 SK-Hep1) was induced by ethidium bromide treatment. The ρ 0 SK-Hep1 cells were resistant to both doxorubicin-and cisplatin-induced apoptosis, while cybrids (SK-Hep1Cyb) prepared by fusing ρ 0 SK-Hep1 cells with platelets showed restored susceptibility to both drugs. We observed P-glycoprotein and MRP1 were both overexpressed in ρ 0 cells, and more P-glycoproteins were localized in the mitochondria and were functionally active. ρ 0 cells showed resistance to chemotherapeutic drug-induced apoptosis. The increased expression and localization of P-glycoproteins in the mitochondria of ρ 0 cells may facilitate the exclusion of chemotherapeutic drugs from the mitochondria to the cytosol.

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Mitochondrial localization and activity of P-glycoprotein in doxorubicin-resistant K562 cells

Cited by 67 publications

References 37 publications

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Mitochondrial localization of P-glycoprotein in the human breast cancer cell line MCF-7/ADM and its functional characterization

Increased P-glycoprotein expression in mitochondria is related to acquired multidrug resistance in human hepatoma cells depleted of mitochondrial DNA

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