| The inhibition of Bid expression by Akt leads to resistance to TRAIL-induced apoptosis in ovarian cancer cells. | |
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MedLine Citation:
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PMID: 20661217 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Epithelial ovarian cancer (EOC) cells often show increased activity of the PI3K/Akt pathway. In addition, we have previously shown that EOC ascites induce Akt activation in the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-sensitive EOC cell line, CaOV3, leading to TRAIL-mediated apoptosis inhibition. In this study, we investigated the role of Akt in intrinsic resistance to TRAIL, which is common in EOC cells. We report that Akt activation reduces the sensitivity of EOC cells to TRAIL. TRAIL-resistant SKOV3ip1 and COV2 cells were sensitized to TRAIL-induced apoptosis by PI3K or Akt inhibitors although inhibition of PI3K/Akt signaling pathway did not interfere with the recruitment and processing of caspase-8 to the death-inducing signaling complex. Conversely, overexpression of Akt1 in TRAIL-sensitive cells promoted resistance to TRAIL. Although the fact that TRAIL-induced caspase-8 activation was observed in both sensitive and resistant cell lines, Bid cleavage occurred only in sensitive cells or in SKOV3ip1 cells treated with LY294002. Bid expression was low in resistant cells and Akt activation downregulated its expression. Depletion of Bid by siRNA in OVCAR3 cells was associated with a decrease in TRAIL-mediated apoptosis. Overexpression of Bid only in SKOV3ip1 cells enhanced TRAIL-induced apoptosis. Simultaneous blockade of Akt pathway further increased TRAIL-induced apoptosis. Thus, Akt acts upstream of mitochondria and inhibits TRAIL-induced apoptosis by decreasing Bid protein levels and possibly inhibiting its cleavage. |
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Authors:
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N Goncharenko-Khaider; D Lane; I Matte; C Rancourt; A Piché |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-26 |
Journal Detail:
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Title: Oncogene Volume: 29 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-07 Completed Date: 2010-11-01 Revised Date: 2010-12-24 |
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: 5523-36 Citation Subset: IM |
Affiliation:
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Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology Apoptosis / drug effects, physiology BH3 Interacting Domain Death Agonist Protein / biosynthesis*, genetics Blotting, Western Cell Line, Tumor Drug Resistance, Neoplasm / genetics* Enzyme Activation / drug effects, genetics Female Gene Expression Gene Expression Regulation, Neoplastic* Humans Immunoprecipitation Ovarian Neoplasms / genetics, metabolism*, pathology Proto-Oncogene Proteins c-akt / genetics, metabolism* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects, genetics TNF-Related Apoptosis-Inducing Ligand / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/BH3 Interacting Domain Death Agonist Protein; 0/BID protein, human; 0/TNF-Related Apoptosis-Inducing Ligand; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
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