| Cellular inhibitor of apoptosis 1 (cIAP-1) degradation by caspase 8 during TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. | |
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MedLine Citation:
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PMID: 20951133 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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TNF-related apoptosis-inducing ligand (TRAIL) is a potential chemotherapeutic agent with high selectivity for malignant cells. Many tumors, however, are resistant to TRAIL cytotoxicity. Although cellular inhibitors of apoptosis 1 and 2 (cIAP-1 and -2) are often over-expressed in cancers, their role in mediating TRAIL resistance remains unclear. Here, we demonstrate that TRAIL-induced apoptosis of liver cancer cells is associated with degradation of cIAP-1 and X-linked IAP (XIAP), whereas cIAP-2 remains unchanged. Lower concentrations of TRAIL causing minimal or no apoptosis do not alter cIAP-1 or XIAP protein levels. Silencing of cIAP-1 expression, but not XIAP or cIAP-2, as well as co-treatment with a second mitochondrial activator of caspases (SMAC) mimetic (which results in rapid depletion of cIAP-1), sensitizes the cells to TRAIL. TRAIL-induced loss of cIAP-1 and XIAP requires caspase activity. In particular, caspase 8 knockdown stabilizes both cIAP-1 and XIAP, while caspase 9 knockdown prevents XIAP, but not cIAP-1 degradation. Cell-free experiments confirmed cIAP-1 is a substrate for caspase 8, with likely multiple cleavage sites. These results suggest that TRAIL-mediated apoptosis proceeds through caspase 8-dependent degradation of cIAP-1. Targeted depletion of cIAP-1 by SMAC mimetics in conjunction with TRAIL may be beneficial for the treatment of human hepatobiliary malignancies. |
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Authors:
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Maria Eugenia Guicciardi; Justin L Mott; Steven F Bronk; Satoshi Kurita; Christian D Fingas; Gregory J Gores |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-14 |
Journal Detail:
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Title: Experimental cell research Volume: 317 ISSN: 1090-2422 ISO Abbreviation: Exp. Cell Res. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-11-24 Completed Date: 2010-12-14 Revised Date: 2012-01-04 |
Medline Journal Info:
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Nlm Unique ID: 0373226 Medline TA: Exp Cell Res Country: United States |
Other Details:
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Languages: eng Pagination: 107-16 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects*,
genetics,
physiology Caspase 8 / antagonists & inhibitors, genetics, metabolism*, physiology Caspase 9 / antagonists & inhibitors, genetics, metabolism Gene Knockdown Techniques Humans Inhibitor of Apoptosis Proteins / antagonists & inhibitors, genetics, metabolism* Protein Processing, Post-Translational / drug effects RNA, Small Interfering / pharmacology Signal Transduction / drug effects, genetics TNF-Related Apoptosis-Inducing Ligand / pharmacology* Tumor Cells, Cultured X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors, genetics |
| Grant Support | |
ID/Acronym/Agency:
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K01 DK079875-05/DK/NIDDK NIH HHS; P30 DK84567/DK/NIDDK NIH HHS; R01 DK063947-09/DK/NIDDK NIH HHS; R01DK63947/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/BIRC3 protein, human; 0/Inhibitor of Apoptosis Proteins; 0/RNA, Small Interfering; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 0/X-Linked Inhibitor of Apoptosis Protein; 0/XIAP protein, human; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspase 9 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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