Differential expression of the multidrug resistance 1 (MDR1) protein in prostate cancer cells is independent from anticancer drug treatment and Y box binding protein 1 (YB-1) activity

Saupe, Madeleine; Rauschenberger, Lisa; Preuß, Melanie; Oswald, Stefan; Fussek, Sebastian; Zimmermann, Uwe; Walther, Reinhard; Knabbe, Cornelius; Burchardt, Martin; Stope, Matthias B.

doi:10.1007/s00345-014-1469-0

Cited by 13 publications

(9 citation statements)

References 23 publications

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“…The results confirmed that the 22Rv1-DR subline was resistant to apoptosis induced by docetaxel treatment. Consistent with the previous reports [23,24], the expression of MDR-1, which is a robust drug pump, was markedly higher in the 22Rv1-DR sublines than that in the parental 22Rv1 (Fig. 1c, sFig.4).…”

Section: Establishment Of Docetaxel-resistant 22rv1 Sublines and Hippsupporting

confidence: 92%

“…However, TEAD1 expression in the nucleus of 22Rv1-DR cells was downregulated in the present study. An in vitro study using Hela cells revealed that the apoptotic role of TEAD1 was modulated by Livin, which is a family member of the inhibitor of apoptosis protein, and YAP1 was not the cofactor involved in this process [24]. The study also discussed that a modest but significant increase in Livin is observed in other types of cancer where TEAD1 is downregulated, such as breast, renal, or bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

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Impact of nuclear YAP1 expression in residual cancer after neoadjuvant chemohormonal therapy with docetaxel for high-risk localized prostate cancer

et al. 2020

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Background: Although docetaxel-based chemohormonal therapy (CHT) is one of the standard treatments for castration-resistant prostate cancer (CRPC), pertinent biomarkers and precise mechanisms involved in the resistance for CHT for CRPC remain unknown. We investigated the relationship between chemohormonal resistance and the expression of steroid receptors and Hippo pathway proteins using a docetaxel-resistant prostate cancer (PCa) cell line and human PCa tissues in patients who underwent surgery with and without neoadjuvant therapy. Methods: A docetaxel-resistant subline (22Rv1-DR) was generated to assess Hippo pathway protein expression and the effect of YAP1 inhibition on cellular characteristics. A tissue microarray with 203 cores from 70 high-risk localized PCa tissues was performed to assess steroid receptor and Hippo pathway protein expressions. Results: Nuclear YAP (nYAP) expression was higher in 22RV-1-DR than in parental 22Rv-1 and YAP1 knockdown suppressed cell proliferation of 22Rv1-DR. Steroid receptor and Hippo pathway protein expressions varied among three different neoadjuvant groups, and nYAP1 expression was the highest in the CHT group. The patients with high nYAP in residual cancer after neoadjuvant CHT had a significantly higher biochemical recurrence (BCR) rate than those with low nYAP1. On multivariate analysis, the high nYAP1 was an independent prognostic factor for BCR. Conclusions: nYAP expression is a potential biomarker in high-risk patients treated with docetaxel-based CHT. Steroid receptors and Hippo pathway proteins may play a role in the chemohormonal resistance in advanced PCa.

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Section: Establishment Of Docetaxel-resistant 22rv1 Sublines and Hippsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Impact of nuclear YAP1 expression in residual cancer after neoadjuvant chemohormonal therapy with docetaxel for high-risk localized prostate cancer

et al. 2020

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“…32 MDR1 is considered to have a minor role for drug resistance in prostate tumor cells. 33 On the other hand, MRP family members are expressed in prostate cancer cells, 34 and we could detect MRP1 protein in LNCaP and 22Rv1 cells by Western blotting (data not shown). Interestingly, GSH has been shown to facilitate drug export mediated by the MRP proteins in tumor cells.…”

Section: Discussionmentioning

confidence: 85%

Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death

et al. 2017

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Drug resistance is a major problem in cancer therapy. A growing body of evidence demonstrates that the tumor microenvironment, including cancer-associated fibroblasts (CAFs), can modulate drug sensitivity in tumor cells. We examined the effect of primary human CAFs on p53 induction and cell viability in prostate cancer cells on treatment with chemotherapeutic drugs. Co-culture with prostate CAFs or CAF-conditioned medium attenuated DNA damage and the p53 response to chemotherapeutic drugs and enhanced prostate cancer cell survival. CAF-conditioned medium inhibited the accumulation of doxorubicin, but not taxol, in prostate cancer cells in a manner that was associated with increased cancer cell glutathione levels. A low molecular weight fraction (<3 kDa) of CAF-conditioned medium had the same effect. CAF-conditioned medium also inhibited induction of reactive oxygen species (ROS) in both doxorubicin- and taxol-treated cancer cells. Our findings suggest that CAFs can enhance drug resistance in cancer cells by inhibiting drug accumulation and counteracting drug-induced oxidative stress. This protective mechanism may represent a novel therapeutic target in cancer.

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“…In general, the high expression of MRP2 and MDR1 in kidney indicates unidirectional efflux of these glucuronides into urine. Although BCRP has small contribution for DHTG efflux, high expression of this transporter in endocrine organs such as placenta [43,44], prostate [45,46] and testis [47,48] can lead to increased clinical significance in these tissues. Notably, genetic polymorphism in BCRP (ABCG2 c.421C > A) which is prevalent in Asian population [49] can influence intracellular concentrations of the most potent androgen, DHTG.…”

Section: Discussionmentioning

confidence: 99%

Major glucuronide metabolites of testosterone are primarily transported by MRP2 and MRP3 in human liver, intestine and kidney

Basit

Gupta

et al. 2019

The Journal of Steroid Biochemistry and Molecular Biology

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Testosterone glucuronide (TG), androsterone glucuronide (AG), etiocholanolone glucuronide (EtioG) and dihydrotestosterone glucuronide (DHTG) are the major metabolites of testosterone (T), which are excreted in urine and bile. Glucuronides can be deconjugated to active androgen in gut lumen after biliary excretion, which in turn can affect physiological levels of androgens. The goal of this study was to quantitatively characterize the mechanisms by which TG, AG, EtioG and DHTG are eliminated from liver, intestine, and kidney utilizing relative expression factor (REF) approach. Using vesicular transport assay with recombinant human MRP2, MRP3, MRP4, MDR1 and BCRP, we first identified that TG, AG, EtioG, and DHTG were primarily substrates of MRP2 and MRP3, although lower levels of transport were also observed with MDR1 and BCRP vesicles. The transport kinetic analyses revealed higher intrinsic clearances of TG by MRP2 and MRP3 as compared to that of DHTG, AG, and EtioG. MRP3 exhibited higher affinity for the transport of the studied glucuronides than MRP2. We next quantified the protein abundances of these efflux transporters in vesicles and compared the same with pooled total membrane fractions isolated from human tissues by quantitative LC-MS/MS proteomics. The fractional contribution of individual transporters (f t ) was estimated by proteomics-based physiological scaling factors, i.e., transporter abundance in whole tissue versus vesicles, and corrected for inside-out vesicles (determined by 5'-nucleotidase assay). The glucuronide metabolites of inactive androgens, AG and EtioG were preferentially transported by MRP3, whereas the glucuronides of active androgens, TG and DHTG were mainly transported by MRP2 in liver. Efflux by bile canalicular transport may indicate the potential role of enterohepatic recirculation in regulating the circulating active androgens after deconjugation in the gut. In intestine, MRP3 possibly contributes most to the efflux of these glucuronides. In kidney, all studied glucuronides seemed to be preferentially effluxed by MRP2 and MDR1 (for EtioG). These REF based analysis need to be confirmed with in vivo findings. Overall, characterization of the efflux mechanisms of T glucuronide metabolites is important for predicting the androgen disposition and interindividual variability, including drugandrogen interaction in humans. The mechanistic data can be extrapolated to other androgen

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Differential expression of the multidrug resistance 1 (MDR1) protein in prostate cancer cells is independent from anticancer drug treatment and Y box binding protein 1 (YB-1) activity

Cited by 13 publications

References 23 publications

Impact of nuclear YAP1 expression in residual cancer after neoadjuvant chemohormonal therapy with docetaxel for high-risk localized prostate cancer

Impact of nuclear YAP1 expression in residual cancer after neoadjuvant chemohormonal therapy with docetaxel for high-risk localized prostate cancer

Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death

Major glucuronide metabolites of testosterone are primarily transported by MRP2 and MRP3 in human liver, intestine and kidney

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