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CD95/Fas signaling in human melanoma cells: conditional expression of CD95L/FasL overcomes the intrinsic apoptosis resistance of malignant melanoma and inhibits growth and progression of human melanoma xenotransplants

Oncogene volume 22, pages 9131–9141 (2003)Cite this article

Abstract

The significance of CD95/Fas ligand expression by melanoma cells has remained a controversial matter in recent years. On the other hand, CD95 activation may represent a powerful tool for eliminating tumor cells. Here, we demonstrate expression of CD95 in 15/17 human melanoma cell lines analysed, but complete lack of CD95 ligand (CD95L). Overexpression of CD95 in a tetracycline-inducible expression system enhanced melanoma cell sensitivity to CD95 ligation but was unable to trigger apoptosis by itself. In clear contrast, all melanoma cells tested responded with increased apoptosis to conditional expression of CD95L (2–10-fold), both after transient and after stable transfection. Activation of caspase-8, Bid cleavage, cytochrome c release and caspase-3 activation followed after CD95L induction indicating a functional CD95-signaling cascade. CD95L was also able to enhance the proapoptotic effect of chemotherapeutics applied in parallel. Nude mouse experiments revealed that tumorigenicity was lost when melanoma xenografts were triggered to express CD95L. In addition, further progression of pre-existing melanomas was inhibited and even regression was seen after induction of CD95L expression. Due to these data, transfection of CD95L proofs as a highly efficient tool against melanoma cells in vitro and in vivo, and targeted expression of CD95L may thus represent a suitable strategy for melanoma therapy.

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Acknowledgements

The study was supported by the Deutsche Krebshilfe/Mildred-Scheel-Stiftung (grant 10-1434-Eb1/2). AMH was a recipient of a scholarship of the Free University of Berlin. We thank Klaus Schulze-Osthoff (Department for Molecular Medicine, Heinrich Heine University Düsseldorf, Germany) for supplying us with caspase-8 antibodies.

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Authors and Affiliations

  1. Department of Dermatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, 14195, Germany

    Jürgen Eberle, Lothar F Fecker, Amir M Hossini, Constantin E Orfanos & Christoph C Geilen

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

    Thomas Wieder & Peter T Daniel

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  1. Jürgen Eberle
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  2. Lothar F Fecker
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Correspondence to Jürgen Eberle.

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Eberle, J., Fecker, L., Hossini, A. et al. CD95/Fas signaling in human melanoma cells: conditional expression of CD95L/FasL overcomes the intrinsic apoptosis resistance of malignant melanoma and inhibits growth and progression of human melanoma xenotransplants. Oncogene 22, 9131–9141 (2003). https://doi.org/10.1038/sj.onc.1207228

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