The role of c-FLIP splice variants in urothelial tumours.
dc.contributor.author | Ewald, F | |
dc.contributor.author | Ueffing, N | |
dc.contributor.author | Brockmann, L | |
dc.contributor.author | Hader, C | |
dc.contributor.author | Telieps, T | |
dc.contributor.author | Schuster, M | |
dc.contributor.author | Schulz, W A | |
dc.contributor.author | Schmitz, I | |
dc.date.accessioned | 2012-05-15T14:32:46Z | |
dc.date.available | 2012-05-15T14:32:46Z | |
dc.date.issued | 2011 | |
dc.identifier.citation | The role of c-FLIP splice variants in urothelial tumours. 2011, 2:e245 Cell Death Dis | en_GB |
dc.identifier.issn | 2041-4889 | |
dc.identifier.pmid | 22190004 | |
dc.identifier.doi | 10.1038/cddis.2011.131 | |
dc.identifier.uri | http://hdl.handle.net/10033/223832 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.rights | Archived with thanks to Cell death & disease | en_GB |
dc.subject.mesh | Aged | en_GB |
dc.subject.mesh | Aged, 80 and over | en_GB |
dc.subject.mesh | Antineoplastic Agents | en_GB |
dc.subject.mesh | Apoptosis | en_GB |
dc.subject.mesh | CASP8 and FADD-Like Apoptosis Regulating Protein | en_GB |
dc.subject.mesh | Cell Line, Tumor | en_GB |
dc.subject.mesh | Cycloheximide | en_GB |
dc.subject.mesh | Female | en_GB |
dc.subject.mesh | Humans | en_GB |
dc.subject.mesh | Male | en_GB |
dc.subject.mesh | Middle Aged | en_GB |
dc.subject.mesh | Protein Isoforms | en_GB |
dc.subject.mesh | RNA Interference | en_GB |
dc.subject.mesh | RNA Splicing | en_GB |
dc.subject.mesh | RNA, Messenger | en_GB |
dc.subject.mesh | RNA, Small Interfering | en_GB |
dc.subject.mesh | TNF-Related Apoptosis-Inducing Ligand | en_GB |
dc.subject.mesh | Urinary Bladder Neoplasms | en_GB |
dc.title | The role of c-FLIP splice variants in urothelial tumours. | en |
dc.type | Article | en |
dc.contributor.department | 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. | en_GB |
dc.identifier.journal | Cell death & disease | en_GB |
refterms.dateFOA | 2018-06-13T05:29:59Z | |
html.description.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. |