Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT

Roundhill, Elizabeth A.; Burchill, S A

doi:10.1038/bjc.2013.168

Cited by 15 publications

(20 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have described MRP-1 in the nucleus (3,4,64), and in this study, we demonstrate coprecipitation and colocalization of HSP70 with MRP-1 in this organelle. This observation suggests that MRP-1 may also be a client protein for HSP70, and supports the hypothesis that multiple proteins of the HSP family may be organelle-specific chaperones for MRP-1.…”

Section: Discussionsupporting

confidence: 81%

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

2015

View full text Add to dashboard Cite

Overexpression of plasma membrane multidrug resistance-associated protein 1 (MRP-1) in Ewing's sarcoma (ES) predicts poor outcome. MRP-1 is also expressed in mitochondria, and we have examined the submitochondrial localization of MRP-1 and investigated the mechanism of MRP-1 transport and role of this organelle in the response to doxorubicin. The mitochondrial localization of MRP-1 was examined in ES cell lines by differential centrifugation and membrane solubilization by digitonin. Whether MRP-1 is chaperoned by heat shock proteins (HSPs) was investigated by immunoprecipitation, immunofluorescence microscopy, and HSP knockout using small hairpin RNA and inhibitors (apoptozole, 17-AAG, and NVPAUY). The effect of disrupting mitochondrial MRP-1-dependent efflux activity on the cytotoxic effect of doxorubicin was investigated by counting viable cell number. Mitochondrial MRP-1 is glycosylated and localized to the outer mitochondrial membrane, where it is coexpressed with HSP90. MRP-1 binds to both HSP90 and HSP70, although only inhibition of HSP90β decreases expression of MRP-1 in the mitochondria. Disruption of mitochondrial MRP-1-dependent efflux significantly increases the cytotoxic effect of doxorubicin (combination index, <0.9). For the first time, we have demonstrated that mitochondrial MRP-1 is expressed in the outer mitochondrial membrane and is a client protein of HSP90β, where it may play a role in the doxorubicin-induced resistance of ES.-Roundhill, E., Turnbull, D., Burchill, S. Localization of MRP-1 to the outer mitochondrial membrane by the chaperone protein HSP90β.

show abstract

Section: Discussionsupporting

confidence: 81%

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

2015

View full text Add to dashboard Cite

show abstract

“…However, previous clinical data suggest that the levels of P-gp have no significant influence on survival in cancer patients undergoing chemotherapy [29]. This implies that other as yet unidentified factors may be involved in the regulation of P-gp function and affect the survival of P-gp positive patients.…”

Section: Discussionmentioning

confidence: 99%

Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers

Zhang

Teng

et al. 2015

Oncotarget

View full text Add to dashboard Cite

The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. In the present study, we showed that c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Our findings identified a new regulatory mechanism of P-gp transport function in multiple drug-resistant gastric and breast cancers.

show abstract

“…Members of the ABC transporter family have the capacity to efflux small molecules, causing drug accumulation in the cell (including the accumulation of anticancer drugs) to decrease, and thus contribute to drug resistance (10). The clinical significance of P-gp and MRP1 in drug resistance is supported by evidence that their expression indicates an adverse prognosis in patients with a range of types of cancer (11,12). Yang et al (13) demonstrated that Nsc23925 could prevent the development of paclitaxel resistance by inhibiting the expression of P-gp and enhancing apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Role of 5‑Aza‑CdR in mitomycin‑C chemosensitivity of T24 bladder cancer cells

et al. 2017

View full text Add to dashboard Cite

Abstract. Chemotherapeutic insensitivity is one of key obstacles to effectively treating muscle invasive bladder cancer. 5-Aza-2'-deoxycytidine (5-Aza-CdR) has been identified as a tumor suppressive agent in various types of cancer. The aim of the present study was to identify the effects of 5-Aza-CdR on the mitomycin-C (MMC) chemosensitivity of T24 bladder cancer cells and investigate the underlying mechanisms. T24 cells were treated with a combination of MMC and 5-Aza-CdR at various concentrations. The rates of proliferation and apoptosis were assessed by an MTT assay and flow cytometry, respectively. The expression of drug resistance-associated proteins, including P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1), and autophagy-associated proteins, including beclin 1, nucleoporin 62 (p62) and autophagy protein 5 (ATG5) were detected with western blotting. Treatment with 5-Aza-CdR significantly promoted the MMC chemosensitivity of T24 cells. The proliferation of T24 cells was significantly inhibited with increasing 5-Aza-CdR concentration, whereas apoptosis was significantly increased. This was associated with the decreased expression of P-gp, MRP1, beclin 1, p62 and ATG5. In conclusion, 5-Aza-CdR enhanced MMC chemosensitivity in bladder cancer T24 cells, which may be caused by the suppression of drug resistance-and autophagy-associated proteins.

show abstract

Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT

Cited by 15 publications

References 64 publications

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers

Role of 5‑Aza‑CdR in mitomycin‑C chemosensitivity of T24 bladder cancer cells

Contact Info

Product

Resources

About