| Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis. | |
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MedLine Citation:
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PMID: 20856198 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Successful treatment of melanoma is still challenging, because metastasis remain chemoresistant and radioresistant. Accordingly, combinational treatments involving death ligands are mandatory. In a recent study from our lab, the majority out of 18 melanoma cell lines remained resistant against treatment with the death ligand TRAIL (tumor necrosis factor related apoptosis inducing ligand). Resistance was shown to be mainly due to incomplete processing of caspase-3 into catalytically inactive p21 by binding of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP). Co-irradiation with sub-lethal ultraviolet (UV) B caused depletion of XIAP resulting in synergistic sensitization of all but two melanoma cell lines to TRAIL. We show here the XIAP depletion to essentially require initial caspase-mediated cleavage, which promotes proteasomal degradation of XIAP. Utilizing specific caspase inhibitors and small interfering RNA-mediated knockdown, we further identified caspase-3 to be responsible for performing the initial cleavage of XIAP after UVB treatment. Additional evidence suggests an accelerated mitochondrial outer membrane permeabilization in response to co-treatment with TRAIL and UVB, which directs the release of XIAP antagonizing factors including Smac. Distraction of XIAP consequently liberates caspase-3 to autocatalytically process into active p17. Activated caspase-3 cleaves XIAP and further enhances its activation in a positive regulatory feedback loop. The molecular mechanism discovered here appears to have broader implications, because cleavage of XIAP was also shown to accompany cisplatin-induced sensitization of melanoma cells to TRAIL. |
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Authors:
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M Hörnle; N Peters; B Thayaparasingham; H Vörsmann; H Kashkar; D Kulms |
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Publication Detail:
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Type: Journal Article Date: 2010-09-20 |
Journal Detail:
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Title: Oncogene Volume: 30 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-02-03 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 575-87 Citation Subset: IM |
Affiliation:
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Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Baden-Württemberg, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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