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Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance

Oncogene volume 20, pages 2749–2760 (2001)Cite this article

Abstract

In this study, we asked whether overexpression of caspase-3, a central downstream executioner of apoptotic pathways, might sensitize breast cancer cells with acquired drug resistance (MT1/ADR) to drug-induced apoptosis. As control, we employed caspase-3 negative and caspase-3-transfected MCF-7 cells. Whereas mock-transfected MCF-7 cells were resistent to epirubicin, etoposide and paclitaxel (taxol), the same drugs led to breakdown of nuclear DNA in caspase-3-transfected MCF-7 cells. MT1/ADR cells express low levels of wild type caspase-3 but show defective caspase activation and apoptosis upon drug exposure. These cells also display a less efficient activation of the mitochondrial permeability transition. Caspase-3-transfected MT1/ADR clones showed a 2.8-fold increase in the protein level and a 3.7-fold higher specific enzyme activity. Procaspase-3 overexpression was not toxic and did not affect background apoptosis. Interestingly, procaspase-3-transfected MT1/ADR cells were more sensitive to cytotoxic drugs as compared with vector-transfected controls and DNA fragmentation nearly reached the levels of the original drug sensitive MT1 cells. Thus, overexpression of caspase-3 enhances chemosensitivity especially in situations where activation of the mitochondrial apoptosome is disturbed.

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Acknowledgements

This work was supported by research grants from the Deutsche Forschungsgemeinschaft (SFB 273 and SFB 506), the European Community TMR Program, the University Medical Center Charité and the Berliner Krebsgesellschaft.

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Author notes

  1. Katrin Friedrich and Thomas Wieder: K Friedrich and T Wieder contributed equally to the present study

Authors and Affiliations

  1. Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Humboldt University Berlin, Berlin, 13125, Germany

    Katrin Friedrich, Thomas Wieder, Clarissa Von Haefen, Silke Radetzki, Bernd Dörken & Peter T Daniel

  2. Department of Immunology and Cell Biology, University of Münster, Münster, 48149, Germany

    Reiner Jänicke & Klaus Schulze-Osthoff

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  1. Katrin Friedrich
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Friedrich, K., Wieder, T., Von Haefen, C. et al. Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance. Oncogene 20, 2749–2760 (2001). https://doi.org/10.1038/sj.onc.1204342

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