| Histone deacetylase inhibitor-induced sensitization to TNFalpha/TRAIL-mediated apoptosis in cervical carcinoma cells is dependent on HPV oncogene expression. | |
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MedLine Citation:
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PMID: 20087862 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Histone-deacetylase (HDAC) inhibitors (HDACi) can block proliferation and induce intrinsic apoptosis in human papillomavirus (HPV)-positive cervical carcinoma cells, independently of copy number and integration locus of the viral DNA. Using HPV18-positive HeLa cells as model systems, we provide evidence that HDAC inhibition leads to transcriptional suppression of c-FLIP, which negatively regulates extrinsic apoptosis by preventing the recruitment of caspase-8 to the death-inducing signaling complex. Consequently, HDACi pretreatment renders cervical cancer cells sensitive to TNFalpha and TRAIL-induced apoptosis. Already 5-hr incubation with TNFalpha or TRAIL was sufficient to eradicate more than 40% of pretreated cells, which are normally completely refractory against respective death-ligands alone even under long-term incubation. Ectopic expression of either short or long splicing variant of c-FLIP, c-FLIP(s) and c-FLIP(L), abrogates sensitization. Notably, combined HDACi/death ligand treatment did not result in eradication of HPV-negative cells, despite the fact that both c-FLIP isoforms were also downregulated. However, knocking down HPV18 E6/E7 transcription by siRNA prevents HDACi/death-ligand mediated apoptosis, indicating that continued viral oncogene expression favors sensitization. Here, the viral oncoprotein E7 seems to play a functional role, since only HPV16 E7-immortalized human keratinocytes underwent significant apoptosis on HDACi/TNFalpha treatment, whereas keratinocytes expressing only HPV16 E6 or primary keratinocytes were refractory under the same experimental conditions. Taken together, HDACi can be considered as an alternative therapeutic option in the treatment of premalignant and malignant lesions. |
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Authors:
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Katalin Darvas; Simone Rosenberger; Dirk Brenner; Cornelius Fritsch; Nadine Gmelin; Peter H Krammer; Frank Rösl |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: International journal of cancer. Journal international du cancer Volume: 127 ISSN: 1097-0215 ISO Abbreviation: Int. J. Cancer Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-07-27 Completed Date: 2010-08-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 1384-92 Citation Subset: IM |
Affiliation:
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Infektionen und Krebs, Deutsches Krebsforschungszentrum, Abteilung Virale Transformationsmechanismen, Heidelberg, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alphapapillomavirus
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genetics* Apoptosis / drug effects* Blotting, Western Female Flow Cytometry Hela Cells Histone Deacetylase Inhibitors / pharmacology* Humans Oncogenes* Reverse Transcriptase Polymerase Chain Reaction TNF-Related Apoptosis-Inducing Ligand / physiology* Tumor Necrosis Factor-alpha / physiology* Uterine Cervical Neoplasms / pathology*, virology |
| Chemical | |
Reg. No./Substance:
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0/Histone Deacetylase Inhibitors; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 0/Tumor Necrosis Factor-alpha |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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