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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

Item Type:Article
Title: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
Creators Name:Eberle, J. and Fecker, L.F. and Hossini, A.M. and Wieder, T. and Daniel, P.T. and Orfanos, C.E. and Geilen, C.C.
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.
Keywords:CD95L/FasL, Melanoma, Transfection, Apoptosis, Animals, Mice
Source:Oncogene
ISSN:0950-9232
Publisher:Nature Publishing Group (U.K.)
Volume:22
Number:57
Page Range:9131-9141
Date:11 December 2003
Official Publication:https://doi.org/10.1038/sj.onc.1207228
PubMed:View item in PubMed

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