MRP1 gene expression level regulates the death and differentiation response of neuroblastoma cells

Peaston, Anne; Gardaneh, Mossa; Franco, Alessandra; Hocker, Jayne E.; Murphy, Kayla; Farnsworth, M L; Catchpoole, Daniel; Haber, Michelle; Norris, Murray D.; Lock, Richard B.; Marshall, Glenn M.

doi:10.1054/bjoc.2001.2144

Cited by 40 publications

(28 citation statements)

References 19 publications

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“…Moreover, the Pgp antagonist verapamil (Kizaki et al, 1996) and MDR1 ribozymes (Matsushita et al, 1998) could restore the sensitivity to ATRA in vitro. Overexpressing the full-length MRP1 cDNA in neuroblastoma cell line conferred ATRA resistance (Peaston et al, 2001). Meanwhile, among MRP family members, MRP3 has the highest degree of structural resemblance to MRP1.…”

Section: Discussionmentioning

confidence: 99%

Role of Pregnane X Receptor in Control of All-TransRetinoic Acid (ATRA) Metabolism and Its Potential Contribution to ATRA Resistance

Wang

Ma²,

Krausz³

et al. 2007

J Pharmacol Exp Ther

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Although all-trans-retinoic acid (ATRA) is an effective treatment for acute promyelocytic leukemia and several solid tumors, its use is limited by resistance due to increased metabolism. The most studied mechanism for ATRA resistance is the autoinduced metabolism regulated by the retinoic acid receptor-CYP26 pathway. However, treatment of cancer is usually not done with a single antineoplastic agent, but with a variety of combined chemotherapy regimens, including several anticancer drugs, and other concomitantly administered supportive drugs. Pregnane X receptor (PXR), an orphan nuclear receptor that functions as a ligandactivated transcription factor, serves as an important xenobiotic sensor regulating metabolism and elimination. Many prescription drugs are PXR ligands, which can activate PXR target genes, including phase I enzyme, phase II enzyme, and transporter genes. The present study was designed to examine the role of PXR in ATRA metabolism. Due to the marked species differences in response to PXR ligands, Pxr-null, wild-type, and PXR-humanized transgenic mouse models were used. In addition to pregnenolone 16␣-carbonitrile, several clinically relevant PXR ligands (rifampicin and dexamethasone) all increased ATRA metabolism both in vitro and in vivo, which was PXR-dependent, and upregulation of Cyp3a was the major contributor. Furthermore, induction of the Mdr1a, Mrp3, and Oatp2 genes was also observed. This study suggested that coadministration of PXR ligands can increase ATRA metabolism through activation of the PXR-CYP3A pathway, which might be a mechanism for some form of ATRA resistance. Other PXR target transporters might also be involved.All-trans retinoic acid (ATRA) is currently used as a chemotherapeutic agent against acute promyelocytic leukemia (APL), breast cancer, Kaposi's sarcoma, and glioma (Muindi et al., 1992b;Defer et al., 1997;Toma et al., 2000;Bernstein et al., 2002). ATRA modulates the transcription of a set of genes associated with cellular apoptosis, growth, and differentiation by binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Incorporation of ATRA into the treatment of APL was the most significant step forward over the past 25 years, resulting in very high rates of complete remission and cure. Unfortunately, despite the general efficacy of ATRA-based therapy, a major drawback to its clinical application is the prompt development of resistance.Several mechanisms have been proposed to explain the involved ATRA resistance arising during cancer therapy, including increased metabolism, sequestration by cellular retinoic acid-binding proteins, decreased uptake by P-glycoprotein (Pgp), and mutations in the ligand-binding domain of promyelocytic leukemia protein-RAR␣ fusion protein, most of which, however, were not well elucidated and still remain controversial when comparing in vitro data with in vivo data (Gallagher, 2002). The only well recognized mechanism is the clear relationship between induction of ATRA metabolism and progressive clinical resista...

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Section: Discussionmentioning

confidence: 99%

Role of Pregnane X Receptor in Control of All-TransRetinoic Acid (ATRA) Metabolism and Its Potential Contribution to ATRA Resistance

Wang

Ma²,

Krausz³

et al. 2007

J Pharmacol Exp Ther

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“…The established association between MYCN amplification and poor outcome may therefore be due, at least in part, to the protection of NB cells against cytotoxic chemotherapy provided by high levels of MRP1. Recent studies suggest that MRP1 may also influence the capacity of NB cells to undergo spontaneous regression in vivo by blocking cell differentiation and apoptosis (Peaston et al, 2001;Kuss et al, 2002). Thus, in addition to mediating multidrug resistance, the transcriptional activation of MRP1 by MYCN may contribute to the clinically aggressive nature of MYCN-amplified NB tumors by modulating NB growth.…”

Section: Discussionmentioning

confidence: 99%

MYCN-mediated regulation of the MRP1 promoter in human neuroblastoma

et al. 2004

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In the childhood cancer neuroblastoma (NB), the level of expression of the multidrug resistance-associated protein (MRP1) gene is strongly correlated with expression of the MYCN oncogene in primary NB tumors, suggesting that MRP1 may be a target for MYCN-mediated gene regulation. In this study, we show that MYCN induction in human NB cells results in increased MRP1 mRNA and protein levels, which in turn is accompanied by increased drug resistance and enhanced MRP1-mediated drug efflux. Furthermore, luciferase activity from MRP1 promoter/luciferase gene reporter constructs was significantly increased in NB cells with exogenous overexpression of MYCN, whereas activity was decreased in NB cells stably transfected with MYCN-antisense vectors. Decreased luciferase activity was observed with promoter constructs that lacked one or two E-box sequences or had E-box double point mutations, while a truncated MRP1 promoter lacking all three E-boxes exhibited only basal levels of activity. Specific electrophoretic mobility shifts of MRP1 E-box sequences were detected with nuclear extracts from NB cells with MYCN overexpression, and complex formation was inhibited with the addition of antibodies directed against MYCN or MYC. These findings indicate that by interacting with E-box elements within the promoter, MYCN can upregulate MRP1 expression and modulate drug resistance in NB.

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“…АВС-транспортеры выбрасывают из клеток такие биологически активные липиды, как простагландины и лейкотриены, которые способны активировать сигнальные каскады, регулирующие про-лиферацию, миграцию, выживаемость клеток [39,40]. АВСС1 в культивируемых клетках нейробластом чело-века влиял на их выживаемость: нокдаун АВСС1 по-тенцировал гибель клеток [41]. Выведение в окружа-ющую опухолевые клетки среду липидов и сигнальных молекул может влиять на экспрессию клетками цито-кинов.…”

Section: механизмы лекарственной устойчивостиunclassified

News in the studies of multidrug resistance of breast cancer cells

Stavrovskaya¹,

Guens²

2015

Usp. mol. onkol

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MRP1 gene expression level regulates the death and differentiation response of neuroblastoma cells

Cited by 40 publications

References 19 publications

Role of Pregnane X Receptor in Control of All-TransRetinoic Acid (ATRA) Metabolism and Its Potential Contribution to ATRA Resistance

Role of Pregnane X Receptor in Control of All-TransRetinoic Acid (ATRA) Metabolism and Its Potential Contribution to ATRA Resistance

MYCN-mediated regulation of the MRP1 promoter in human neuroblastoma

News in the studies of multidrug resistance of breast cancer cells

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