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Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk / Bik

Oncogene volume 24, pages 7369–7380 (2005)Cite this article

Abstract

The proapoptotic BH3-only protein natural born killer / Bcl-2 interacting killer (Nbk / Bik) has been described to inhibit Bcl-2 and Bcl-xL, thereby supporting the death promoting ability of Bax. In order to evaluate its function in melanoma, we investigated the response after Nbk / Bik overexpression in cultured human melanoma cells and in a melanoma mouse model. Untransfected melanoma cell lines expressed Nbk / Bik only weakly at the mRNA and protein level. Conditional expression of Nbk / Bik by applying the inducible tetracycline-responsive expression system triggered apoptosis and enhanced sensitivity to proapoptotic stimuli as to agonistic CD95 activation and to chemotherapeutics etoposide, doxorubicin and pamidronate. For investigating the effects of Nbk / Bik in vivo, stably transfected melanoma cells were subcutaneously injected into nude mice. Significantly delayed tumor growth was the result when mice received doxycycline for induction of Nbk / Bik expression. By investigating the mechanism of Nbk / Bik-induced cell death, typical hallmarks of apoptosis such as DNA fragmentation and chromatin condensation were seen after induction. Interestingly, no indications for cytochrome c release and caspase processing were found, and selective caspase inhibition remained without effect. These data indicate the high potential of Nbk / Bik in regulating apoptosis in melanoma by a caspase-independent pathway and may corroborate the potency of novel antimelanoma strategies based on activation of BH3-only proteins such as Nbk / Bik.

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Acknowledgements

Malte Oppermann was a recipient of a scholarship from the Deutsche Forschungsgemeinschaft (GRK 276 / 3). The study was further supported by the Deutsche Krebshilfe / Mildred-Scheel-Stiftung (Grant 10–1434-Eb1 / 2), the Deutsche Forschungsgemeinschaft (SFB 366, TP B8) and the Sonnenfeld-Stiftung, Berlin.

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Authors and Affiliations

  1. Department of Dermatology and Allergy, Skin cancer center, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

    Malte Oppermann, Christoph C Geilen, Lothar F Fecker & Jürgen Eberle

  2. Clinical and Molecular Oncology, Charité – Universitätsmedizin Berlin, Campus Buch, Berlin, Germany

    Bernhard Gillissen & Peter T Daniel

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  1. Malte Oppermann
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  2. Christoph C Geilen
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Correspondence to Jürgen Eberle.

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Oppermann, M., Geilen, C., Fecker, L. et al. Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk / Bik. Oncogene 24, 7369–7380 (2005). https://doi.org/10.1038/sj.onc.1208890

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