| Nimbolide sensitizes human colon cancer cells to TRAIL through reactive oxygen species- and ERK-dependent up-regulation of death receptors, p53, and Bax. | |
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MedLine Citation:
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PMID: 21078664 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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TNF-related apoptosis-inducing ligand (TRAIL) shows promise as a cancer treatment, but acquired tumor resistance to TRAIL is a roadblock. Here we investigated whether nimbolide, a limonoid, could sensitize human colon cancer cells to TRAIL. As indicated by assays that measure esterase activity, sub-G(1) fractions, mitochondrial activity, and activation of caspases, nimbolide potentiated the effect of TRAIL. This limonoid also enhanced expression of death receptors (DRs) DR5 and DR4 in cancer cells. Gene silencing of the receptors reduced the effect of limonoid on TRAIL-induced apoptosis. Using pharmacological inhibitors, we found that activation of ERK and p38 MAPK was required for DR up-regulation by nimbolide. Gene silencing of ERK abolished the enhancement of TRAIL-induced apoptosis. Moreover, our studies indicate that the limonoid induced reactive oxygen species production, which was required for ERK activation, up-regulation of DRs, and sensitization to TRAIL; these effects were mimicked by H(2)O(2). In addition, nimbolide down-regulated cell survival proteins, including I-FLICE, cIAP-1, cIAP-2, Bcl-2, Bcl-xL, survivin, and X-linked inhibitor of apoptosis protein, and up-regulated the pro-apoptotic proteins p53 and Bax. Interestingly, p53 and Bax up-regulation by nimbolide was required for sensitization to TRAIL but not for DR up-regulation. Overall, our results indicate that nimbolide can sensitize colon cancer cells to TRAIL-induced apoptosis through three distinct mechanisms: reactive oxygen species- and ERK-mediated up-regulation of DR5 and DR4, down-regulation of cell survival proteins, and up-regulation of p53 and Bax. |
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Authors:
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Subash C Gupta; Simone Reuter; Kanokkarn Phromnoi; Byoungduck Park; Padmanabhan S Hema; Mangalam Nair; Bharat B Aggarwal |
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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: 2010-11-15 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-10 Completed Date: 2011-03-02 Revised Date: 2012-01-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 1134-46 Citation Subset: IM |
Affiliation:
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Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenocarcinoma
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drug therapy*,
metabolism,
pathology Antineoplastic Agents / pharmacology* Apoptosis / drug effects, physiology Breast Neoplasms Colonic Neoplasms / drug therapy*, metabolism, pathology Extracellular Signal-Regulated MAP Kinases / metabolism* HCT116 Cells HT29 Cells Humans Kidney Neoplasms Leukemia, Myelogenous, Chronic, BCR-ABL Positive Limonins / pharmacology* Lung Neoplasms Multiple Myeloma Pancreatic Neoplasms Reactive Oxygen Species / metabolism Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism TNF-Related Apoptosis-Inducing Ligand / metabolism* Tumor Suppressor Protein p53 / metabolism bcl-2-Associated X Protein / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA-124787-01A2/CA/NCI NIH HHS; CA016672/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Limonins; 0/Reactive Oxygen Species; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFRSF10A protein, human; 0/TNFSF10 protein, human; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein; 25990-37-8/nimbolide; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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