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The role of c-FLIP splice variants in urothelial tumours.

Ewald, F
; 
Ueffing, N
; 
Brockmann, L
; 
Hader, C
; 
Telieps, T
; 
Schuster, M
; 
Schulz, W A
; 
Schmitz, I
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2011
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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-FLIP(long) (c-FLIP(L)) and c-FLIP(short) (c-FLIP(S)), which can have opposing functions. We observed diminished expression of the c-FLIP(L) isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIP(S) 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-FLIP(L) 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-FLIP(L) isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours.
Citation
The role of c-FLIP splice variants in urothelial tumours. 2011, 2:e245 Cell Death Dis
Affiliation
Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg and Department of Immune Control, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany.
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Cell death & disease
URI
http://hdl.handle.net/10033/223832
DOI
10.1038/cddis.2011.131
PubMed ID
22190004
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Article
Language
en
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2041-4889
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publications of the AG system-oriented immunology and infection research (SIME)