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miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells

Oncogene volume 33, pages 3717–3729 (2014)Cite this article

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Abstract

Chemotherapy is the most common treatment for cancer. However, multidrug resistance (MDR) remains a major obstacle to effective chemotherapy, limiting the efficacy of both conventional chemotherapeutic and novel biologic agents. The constitutive androstane receptor (CAR), a xenosensor, is a key regulator of MDR. It functions in xenobiotic detoxification by regulating the expression of phase I drug-metabolizing enzymes and ATP-binding cassette (ABC) transporters, whose overexpression in cancers and whose role in drug resistance make them potential therapeutic targets for reducing MDR. MicroRNAs (miRNAs) are endogenous negative regulators of gene expression and have been implicated in most cellular processes, including drug resistance. Here, we report the inversely related expression of miR-137 and CAR in parental and doxorubicin-resistant neuroblastoma cells, wherein miR-137 is downregulated in resistant cells. miR-137 overexpression resulted in downregulation of CAR protein and mRNA (via mRNA degradation); it sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis and increased G2-phase cell cycle arrest) and reduced the in vivo growth rate of neuroblastoma xenografts. We observed similar results in cellular models of hepatocellular and colon cancers, indicating that the doxorubicin-sensitizing effect of miR-137 is not tumor type-specific. Finally, we show for the first time a negative feedback loop whereby miR-137 downregulates CAR expression and CAR downregulates miR-137 expression. Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells. These findings demonstrate that miR-137 is a crucial regulator of cancer response to doxorubicin treatment, and they identify miR-137 as a highly promising target to reduce CAR-driven doxorubicin resistance.

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Acknowledgements

We thank Drs David Moore and Hongbing Wang for plasmids; the Flow Cytometry and Cell Sorting Shared Resource, the St Jude Animal Resources Center and Veterinary Pathology Core for technical assistance; other members of the Chen group and Drs Yong Li, John Schuetz, and Kip Guy for valuable discussions; and Sharon Naron for editing the manuscript. This work was supported by the American Lebanese Syrian Associated Charities (ALSAC), St Jude Children’s Research Hospital (SJCRH), National Cancer Institute grant P30CA027165, National Institute of General Medical Sciences Grant GM086415, the Hilfe für krebskranke Kinder Frankfurt eV, the Frankfurter Stiftung für krebskranke Kinder, and the Kent Cancer Trust.

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  1. Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, TN, USA

    A A Takwi, Y-M Wang, J Wu & T Chen

  2. School of Biosciences, University of Kent, Canterbury, UK

    M Michaelis

  3. Institute for Medical Virology, Clinics of the Goethe-University, Frankfurt am Main, Germany

    J Cinatl

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  1. A A Takwi
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Takwi, A., Wang, YM., Wu, J. et al. miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells. Oncogene 33, 3717–3729 (2014). https://doi.org/10.1038/onc.2013.330

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