P‐glycoprotein down‐regulates expression of breast cancer resistance protein in a drug‐free state

Bark, Hyun; Xu, Haidong; Kim, Sang-Hyun; Yun, Jisoo; Choi, Cheol-Hee

doi:10.1016/j.febslet.2008.06.036

Cited by 17 publications

(13 citation statements)

References 15 publications

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“…In our current study, for the first time, we have confirmed that overexpression of miR200c decreased the levels of JNK2, p-JNK, p-c-Jun, ABCB1/P-gp, and MMP-2/-9 in MDR colorectal cancer cells. In addition, our analyses showed that miR200c did not affect other critical transporters in MDR such as MRP-1, MRP-2, and BCRP, consistent with the reported function of JNK (39)(40)(41). We also found that ATF-2 and Elk-1, the other two major players downstream of activated JNK in MDR colorectal cancer cells, were not affected by miR200c on the expression levels, suggesting that miR200c might selectively target the JNK2/p-JNK/p-c-Jun signaling pathway.…”

Section: Discussionsupporting

confidence: 73%

miR200c Attenuates P-gp–Mediated MDR and Metastasis by Targeting JNK2/c-Jun Signaling Pathway in Colorectal Cancer

Sui

Cai

Shu

et al. 2014

Molecular Cancer Therapeutics

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MicroRNA-200c (miR200c) recently emerged as an important regulator of tumorigenicity and cancer metastasis; however, its role in regulating multidrug resistance (MDR) remains unknown. In the current study, we found that the expression levels of miR200c in recurrent and metastatic colorectal cancers were significantly lower, whereas the JNK2 expression was higher compared with primary tumors. We showed that in MDR colorectal cancer cells, miR200c targeted the 3 0 untranslated region of the JNK2 gene. Overexpression of miR200c attenuated the levels of p-JNK, p-c-Jun, P-gp, and MMP-2/-9, the downstream factors of the JNK signaling pathway, resulting in increased sensitivity to chemotherapeutic drugs, which was accompanied by heightened apoptosis and decreased cell invasion and migration. Moreover, in an orthotopic MDR colorectal cancer mouse model, we demonstrated that overexpression of miR200c effectively inhibited the tumor growth and metastasis. At last, in the tumor samples from patients with locally advanced colorectal cancer with routine postsurgical chemotherapy, we observed an inverse correlation between the levels of mRNA expression of miR200c and JNK2, ABCB1, and MMP-9, thus predicting patient therapeutic outcomes. In summary, we found that miR200c negatively regulated the expression of JNK2 gene and increased the sensitivity of MDR colorectal cancer cells to chemotherapeutic drugs, via inhibiting the JNK2/p-JNK/p-c-Jun/ ABCB1 signaling. Restoration of miR200c expression in MDR colorectal cancer may serve as a promising therapeutic approach in MDR-induced metastasis.

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Section: Discussionsupporting

confidence: 73%

miR200c Attenuates P-gp–Mediated MDR and Metastasis by Targeting JNK2/c-Jun Signaling Pathway in Colorectal Cancer

Sui

Cai

Shu

et al. 2014

Molecular Cancer Therapeutics

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“…We discovered that certain ER stress inducers (tunicamycin and THAPS) could increase recombinant ABC transporter expression. It has been shown that these agents can induce P-gp mRNA and protein expression (Bark et al, 2008). The concentration of the compounds we used did not compromise the TEER resistance of the cell monolayer.…”

Section: Discussionmentioning

confidence: 96%

“…Our previous study showed that ABCG2 expression was suppressed in the presence of P-gp in HeLa cells (Shukla et al, 2012), and it was suggested that expression of Pgp and ABCG2 is somewhat linked (Bark et al, 2008). Therefore, we investigated whether P-gp and breast cancer resistance protein expression is affected in the polarized cells.…”

Section: Resultsmentioning

confidence: 99%

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Using the BacMam Baculovirus System to Study Expression and Function of Recombinant Efflux Drug Transporters in Polarized Epithelial Cell Monolayers

Fung

Kapoor

Pixley

et al. 2015

Drug Metabolism and Disposition

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The ATP-binding cassette (ABC) transporter superfamily includes several membrane-bound proteins that are critical to drug pharmacokinetics and disposition. Pharmacologic evaluation of these proteins in vitro remains a challenge. In this study, human ABC transporters were expressed in polarized epithelial cell monolayers transduced using the BacMam baculovirus gene transfer system. The purpose of the study was to evaluate the efficacy of BacMam baculovirus to transduce cells grown in monolayers. In a porcine kidney cell line, LLC-PK1 cells, baculoviral transduction is successful only via the apical side of a polarized monolayer. We observed that recombinant ABC transporters were expressed on the cell surface with post-translational modification. Furthermore, sodium butyrate played a critical role in recombinant protein expression, and preincubation in the presence of tunicamycin or thapsigargin enhanced protein expression. Cells overexpressing human P-glycoprotein (P-gp) showed vectorial basolateral-to-apical transport of [ 3 H]-paclitaxel, which could be reversed by the inhibitor tariquidar. Similarly, coexpression of human P-gp and ABCG2 in LLC-PK1 cells resulted in higher transport of mitoxantrone, which is a substrate for both transporters, than in either P-gp-or ABCG2-expressing cells alone. Taken together, our results indicate that a high level of expression of efflux transporters in a polarized cell monolayer is technically feasible with the BacMam baculovirus system

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“…They found an inverse relation between ABCB1 and ABCG2 expression in the absence of doxorubicin [43]. Similarly, Cisternino et al [44] found that defective ABCB1 was associated with increased ABCG2 mRNA at the mouse blood-brain barrier.…”

Section: Discussionmentioning

confidence: 96%

Possible Role of microRNA-122 in Modulating Multidrug Resistance of Hepatocellular Carcinoma

et al. 2017

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Hepatocellular carcinoma (HCC) is a hypervascular primary liver cancer characterized by rapid progression, besides, resistance to traditional chemotherapeutic agents. It has been shown that microRNAs play critical roles in regulation of tumor cell sensitivity to drugs through modulating the expression of genes involved in drug transport. The present study investigated whether restoration of miR-122 in HCC cells could alter the cell cycle distribution and the expression of multidrug resistance (MDR)-related genes (ABCB1, ABCC1, ABCG2 and ABCF2). After overexpression of miR-122 in HepG2 cells treated or untreated with doxorubicin doses, total RNAs and protein extracts were isolated for application of QRT-PCR and western blotting techniques. Moreover, cell cycle distribution was monitored by flow cytometry. Our results revealed that, the over expression of miR-122 in HepG2 cells treated or untreated with doxorubicin could modulate the sensitivity of cells to chemotherapeutic drug through downregulation of MDR-related genes, ABCB1 and ABCF2. Interpretation of cell cycle distribution revealed that, the anti-proliferative effect of miR-122 is associated with the accumulation of cells in G/G1 phase. Moreover, treatment with miR-122 and doxorubicin resulted in high percentage of HCC cells in G/G1 phase. Taken together, our findings revealed that, overexpression of miR-122 inhibited HCC cell growth by inducing cell cycle arrest and this arrest is associated with down-regulation of MDR-related genes.

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P‐glycoprotein down‐regulates expression of breast cancer resistance protein in a drug‐free state

Cited by 17 publications

References 15 publications

miR200c Attenuates P-gp–Mediated MDR and Metastasis by Targeting JNK2/c-Jun Signaling Pathway in Colorectal Cancer

miR200c Attenuates P-gp–Mediated MDR and Metastasis by Targeting JNK2/c-Jun Signaling Pathway in Colorectal Cancer

Using the BacMam Baculovirus System to Study Expression and Function of Recombinant Efflux Drug Transporters in Polarized Epithelial Cell Monolayers

Possible Role of microRNA-122 in Modulating Multidrug Resistance of Hepatocellular Carcinoma

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