Expression of Multidrug Resistance Related Proteins and Proliferative Activity Is Increased in Advanced Clinical Prostate Cancer

Brussel, J.P. van; Steenbrugge, G.J. van; Krimpen, C. van; Bogdanowicz, Jacques F.A.T.; Kwast, Theo H. van der; Schröder, Fritz H.; Mickisch, G.

doi:10.1097/00005392-200101000-00032

Cited by 57 publications

(44 citation statements)

References 23 publications

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“…10,11 In leukemia and many types of cancers, including hepatocellular, colorectal and prostate cancer, P-gp has been demonstrated to promote cell survival. [12][13][14][15] Until now, no data are available on the possible anti-apoptotic role of P-gp in gastric carcinogenesis.…”

mentioning

confidence: 99%

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

Rocco

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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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mentioning

confidence: 99%

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

Rocco

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Liguori

et al. 2012

Laboratory Investigation

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“…Hence, targeting multiple pathways could be a more effective approach. In advanced prostate cancer, MDR-ABC transporters are highly expressed [57]. Here, we provide a proof of concept, that prostate luminal cell differentiation can be augmented by MDR-ABC transporter blockade.…”

Section: Enhanced Differentiation With Mdr-abc Efflux Inhibition May mentioning

confidence: 81%

Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation

Samant

Jackson

Felix

et al. 2015

Stem Cells and Development

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Multi-drug resistance (MDR)-ATP binding cassette (ABC) transporters, ABCB1, ABCC1, and ABCG2 participate in the efflux of steroid hormones, estrogens, and androgens, which regulate prostate development and differentiation. The role of MDR-ABC efflux transporters in prostate epithelial proliferation and differentiation remains unclear. We hypothesized that MDR-ABC transporters regulate prostate differentiation and epithelium regeneration. Prostate epithelial differentiation was studied using histology, sphere formation assay, and prostate regeneration induced by cycles of repeated androgen withdrawal and replacement. Embryonic deletion of Abcg2 resulted in a decreased number of luminal cells in the prostate and increased sphere formation efficiency, indicating an imbalance in the prostate epithelial differentiation pattern. Decreased luminal cell number in the Abcg2 null prostate implies reduced differentiation. Enhanced sphere formation efficiency in Abcg2 null prostate cells implies activation of the stem/progenitor cells. Prostate regeneration was associated with profound activation of the stem/progenitor cells, indicating the role of Abcg2 in maintaining stem/progenitor cell pool. Since embryonic deletion of Abcg2 may result in compensation by other ABC transporters, pharmacological inhibition of MDR-ABC efflux was performed. Pharmacological inhibition of MDR-ABC efflux enhanced prostate epithelial differentiation in sphere culture and during prostate regeneration. In conclusion, Abcg2 deletion leads to activation of the stem/progenitor cells and enhances differentiating divisions; and pharmacological inhibition of MDR-ABC efflux leads to epithelial differentiation. Our study demonstrates for the first time that MDR-ABC efflux transporter inhibition results in enhanced prostate epithelial cell differentiation.

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“…Correspondingly, the NS and GL261 cells, besides showing the highest Mrp1 expression levels, were also the population with more BrdU+ cells, suggesting that multidrug transporters not only give resistance, but also allow and are needed for NSPC [66] and tumor cell [67] proliferation. Autophagy has been implicated in normal brain development [68,69] , and an abnormality in the autophagic process is related to malignant diseases.…”

Section: Protein Signatures With Gl261mentioning

confidence: 96%

Early Differentiating Mouse Astroglial Progenitors Share Common Protein Signatures with GL261 Glioma Cells

Brites¹

2016

JSRB

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Neural stem cells (NSC) biology is being applied to tumor research because these cells have been shown to share key properties with cancer cells. Gliomas represent the most common brain tumor, and neural stem/progenitor cells (NSPC) or early-differentiated cell type lineages may be on its origin. Here, we identified the developmental stage of the differentiation process of NSC into astrocytes that showed the highest number of tumorigenic similarities.NSPC were grown as neurospheres and astroglial differentiation was induced during 7 days in vitro (DIV). Cellular characterization was evaluated by specific neural markers at two developmental windows, i.e. NSPC/astrocyte progenitors from neurospheres until 3 DIV, and differentiating astrocytes thereafter. Predominance of immature Sox2-positive cells was verified in the first window and a prevalence of GFAP-positive cells in the second one. We then compared some tumor-related markers in GL261 glioma cells with such differentiating periods. The early progenitor cells (until 2 DIV) were those with the closest resemblances to the glioma cell line regarding BrdU incorporation, expression of microtubule-associated protein light chain 3 and of angiogenic factors (VEGF/VEGFR2), as well as S100B release. Our results suggest that early differentiating astroglial progenitors may be more susceptible to malignant transformation.

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Expression of Multidrug Resistance Related Proteins and Proliferative Activity Is Increased in Advanced Clinical Prostate Cancer

Cited by 57 publications

References 23 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

Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation

Early Differentiating Mouse Astroglial Progenitors Share Common Protein Signatures with GL261 Glioma Cells

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