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NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells

Oncogene volume 22, pages 90–97 (2003)Cite this article

Abstract

The ubiquitous NF-κB transcription factor has been reported to inhibit apoptosis and to induce drug resistance in cancer cells. Drug resistance is the major reason for cancer therapy failure and neoplastic cells often develop multiple mechanisms of drug resistance during tumor progression. We observed that NF-κB or P-glycoprotein inhibition in the HCT15 colon cancer cells led to increased apoptotic cell death in response to daunomycin treatment. Interestingly, NF-κB inhibition through transfection of a plasmid coding for a mutated IκB-α inhibitor increased daunomycin cell uptake. Indeed, the inhibition of NF-κB reduced mdr1 mRNA and P-glycoprotein expression in HCT15 cells. We identified a consensus NF-κB binding site in the first intron of the human mdr1 gene and demonstrated that NF-κB complexes could bind with this intronic site. Moreover, NF-κB transactivates an mdr1 promoter luciferase construct. Our data thus demonstrate a role for NF-κB in the regulation of the mdr1 gene expression in cancer cells and in drug resistance.

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Abbreviations

NF-κB:

nuclear factor-κB

IκB:

inhibitor of κB

MDR:

multidrug resistance

P-gp:

P-glycoprotein

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Acknowledgements

MF and NJ are Senior Research Assistants, AC and M-P M are Research Associates at the National Fund for Scientific Research (FNRS, Belgium). M B-A is supported by a Télévie fellowship (FNRS, Belgium). This research was supported by grants from the Centre Anti-Cancereux (Liége, Belgium) and the FRSM (Belgium).

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Authors and Affiliations

  1. Center for Cellular and Molecular Therapy, University of Liège, Belgium

    Mohamed Bentires-Alj, Marianne Fillet, Alain Chariot, Biserka Relic, Jacques Gielen, Marie-Paule Merville & Vincent Bours

  2. Laboratory of Molecular Biology, INSERM Unit 402, Saint-Antoine Hospital, Paris, France

    Veronique Barbu

  3. Center for Research in Experimental Cancerology, University of Liege, Belgium

    Nathalie Jacobs

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  1. Mohamed Bentires-Alj
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Correspondence to Vincent Bours.

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Bentires-Alj, M., Barbu, V., Fillet, M. et al. NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 22, 90–97 (2003). https://doi.org/10.1038/sj.onc.1206056

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