The role of c-FLIP splice variants in urothelial tumours |
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Authors: | F Ewald N Ueffing L Brockmann C Hader T Telieps M Schuster W A Schulz I Schmitz |
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Institution: | 1.Laboratory of Systems-oriented Immunology and Inflammation Research, Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg and Department of Immune Control, Helmholtz Centre for Infection Research, Inhoffenstr 7, D-38124 Braunschweig, Germany;2.Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Universitaetsstr 1, D-40225 Duesseldorf, Germany;3.Department of Urology, Heinrich Heine University, D-40225 Duesseldorf, Germany |
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Abstract: | Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells. One important regulator of apoptosis is the cellular FLICE-inhibitory protein (c-FLIP), which is overexpressed, for example, in melanoma and Hodgkin''s lymphoma cells. Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis. In particular, we investigated the role of the c-FLIP splice variants c-FLIPlong (c-FLIPL) and c-FLIPshort (c-FLIPS), which can have opposing functions. We observed diminished expression of the c-FLIPL isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIPS was unchanged. Overexpression and RNA interference studies in urothelial cell lines nevertheless demonstrated that c-FLIP remained a crucial factor conferring resistance towards induction of apoptosis by death ligands CD95L and TRAIL. Isoform-specific RNA interference showed c-FLIPL to be of particular importance. Thus, urothelial carcinoma cells appear to fine-tune c-FLIP expression to a level sufficient for protection against activation of apoptosis by the extrinsic pathway. Therefore, targeting c-FLIP, and especially the c-FLIPL isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours. |
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Keywords: | apoptosis bladder cancer cancer therapy resistance death receptor |
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