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  • Original Paper
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The apoptosis promoting Bcl-2 homologues Bak and Nbk/Bik overcome drug resistance in Mdr-1-negative and Mdr-1-overexpressing breast cancer cell lines

Oncogene volume 21, pages 227–238 (2002)Cite this article

Abstract

We previously demonstrated that the forced expression of pro-caspase-3 can revert acquired chemoresistance in MT1-Adr breast cancer cells which show a defective activation of the mitochondrial pathway of apoptosis. We now asked whether the manipulation of mitochondrial apoptosis signaling can revert different types of drug resistance, i.e. the resistance due to impaired mitochondrial activation in the MT1-Adr cells and the resistance in MT3-Adr cells which is caused by increased expression of the Mdr-1/p-glycoprotein ABC transporter. Here we show that Bcl-2 overexpression is the underlying cause for the resistant phenotype in the MT1-Adr cells. Overexpression of the apoptosis-promoting Bax homologue Bak or the BH3 only protein Nbk/Bik reverts, as expected, acquired drug resistance in the MT1-Adr cells as recently demonstrated for pro-caspase-3. Moreover, we show that both apoptosis-promoters, Nbk/Bik and Bak, antagonize acquired chemoresistance for epirubicin-mediated apoptosis in MT3-Adr breast cancer cells. Neither drug uptake nor drug efflux were influenced by Bak or Nbk/Bik. Thus, our data show that manipulation of the downstream apoptosis signaling cascade by Bak and Nbk/Bik can overcome not only drug resistance due to mitochondrial apoptosis deficiency (in the MT1-Adr cells) but also classical, i.e. efflux-mediated, resistance for drug-induced cell death in the MT3-Adr cell line. Nbk/Bik and Bak could therefore be target genes to increase chemosensitivity and overcome different types of drug resistance.

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Acknowledgements

Part of this work was supported by the European Training and Mobility of Researchers (TMR) program and by the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Department of Hematology, Oncology, and Tumor Immunology, Charité - Campus Berlin-Buch, Humboldt University, Berlin-Buch, 13125, Germany

    Silke Radetzki, Claus-Henning Köhne, Clarissa von Haefen, Bernhard Gillissen, Isrid Sturm, Bernd Dörken & Peter T Daniel

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  1. Silke Radetzki
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  2. Claus-Henning Köhne
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Correspondence to Peter T Daniel.

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Radetzki, S., Köhne, CH., von Haefen, C. et al. The apoptosis promoting Bcl-2 homologues Bak and Nbk/Bik overcome drug resistance in Mdr-1-negative and Mdr-1-overexpressing breast cancer cell lines. Oncogene 21, 227–238 (2002). https://doi.org/10.1038/sj.onc.1205010

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