2.50
Hdl Handle:
http://hdl.handle.net/10033/223832
Title:
The role of c-FLIP splice variants in urothelial tumours.
Authors:
Ewald, F; Ueffing, N; Brockmann, L; Hader, C; Telieps, T; Schuster, M; Schulz, W A; Schmitz, I
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.
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.
Citation:
The role of c-FLIP splice variants in urothelial tumours. 2011, 2:e245 Cell Death Dis
Journal:
Cell death & disease
Issue Date:
2011
URI:
http://hdl.handle.net/10033/223832
DOI:
10.1038/cddis.2011.131
PubMed ID:
22190004
Type:
Article
Language:
en
ISSN:
2041-4889
Appears in Collections:
publications of the research group (SIME)

Full metadata record

DC FieldValue Language
dc.contributor.authorEwald, Fen_GB
dc.contributor.authorUeffing, Nen_GB
dc.contributor.authorBrockmann, Len_GB
dc.contributor.authorHader, Cen_GB
dc.contributor.authorTelieps, Ten_GB
dc.contributor.authorSchuster, Men_GB
dc.contributor.authorSchulz, W Aen_GB
dc.contributor.authorSchmitz, Ien_GB
dc.date.accessioned2012-05-15T14:32:46Z-
dc.date.available2012-05-15T14:32:46Z-
dc.date.issued2011-
dc.identifier.citationThe role of c-FLIP splice variants in urothelial tumours. 2011, 2:e245 Cell Death Disen_GB
dc.identifier.issn2041-4889-
dc.identifier.pmid22190004-
dc.identifier.doi10.1038/cddis.2011.131-
dc.identifier.urihttp://hdl.handle.net/10033/223832-
dc.description.abstractDeregulation 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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Cell death & diseaseen_GB
dc.subject.meshAgeden_GB
dc.subject.meshAged, 80 and overen_GB
dc.subject.meshAntineoplastic Agentsen_GB
dc.subject.meshApoptosisen_GB
dc.subject.meshCASP8 and FADD-Like Apoptosis Regulating Proteinen_GB
dc.subject.meshCell Line, Tumoren_GB
dc.subject.meshCycloheximideen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshHumansen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiddle Ageden_GB
dc.subject.meshProtein Isoformsen_GB
dc.subject.meshRNA Interferenceen_GB
dc.subject.meshRNA Splicingen_GB
dc.subject.meshRNA, Messengeren_GB
dc.subject.meshRNA, Small Interferingen_GB
dc.subject.meshTNF-Related Apoptosis-Inducing Liganden_GB
dc.subject.meshUrinary Bladder Neoplasmsen_GB
dc.titleThe role of c-FLIP splice variants in urothelial tumours.en
dc.typeArticleen
dc.contributor.departmentInstitute 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.journalCell death & diseaseen_GB

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