| Gamma-tocotrienol promotes TRAIL-induced apoptosis through reactive oxygen species/extracellular signal-regulated kinase/p53-mediated upregulation of death receptors. | |
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MedLine Citation:
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PMID: 20682650 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is in clinical trials for cancer therapy, but its anticancer potential is limited by the development of resistance. We investigated the ability of tocotrienol (T3), an unsaturated vitamin E present in palm oil, rice bran, barley, oats, and wheat germ, to sensitize tumor cells to TRAIL. Results from esterase staining, colony formation, caspase activation, and sub-G(1) cell cycle arrest revealed that gamma-T3 can sensitize human colon cancer cells to TRAIL. When examined for the mechanism, we found that gamma-T3 significantly downregulated the expression of antiapoptotic proteins (c-IAP2 and Bcl-xL). We also found that gamma-T3, but not tocopherol, induced the expression of the TRAIL receptors death receptor (DR)-4 and DR5. This induction was not cell type specific, as upregulation was also found in pancreatic, kidney, and leukemic cells. Upregulation of DRs by gamma-T3 required the production of reactive oxygen species (ROS), and sequestering of ROS abolished both upregulation of the receptors and potentiation of TRAIL-induced apoptosis. Induction of DRs by gamma-T3 also required activation of extracellular signal-regulated kinase 1 (ERK1), as silencing of ERK1 by specific siRNA abrogated the upregulation of TRAIL receptors. Further, induction of DRs by gamma-T3 required the expression of p53 and Bax, as no induction of the receptors was found in colon cancer cells with deletion of these genes. Overall, our results show that gamma-T3 sensitizes tumor cells to TRAIL by upregulating DRs through the ROS/ERK/p53 pathway and by downregulating cell survival proteins. |
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Authors:
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Ramaswamy Kannappan; Jayaraj Ravindran; Sahdeo Prasad; Bokyung Sung; Vivek R Yadav; Simone Reuter; Madan M Chaturvedi; Bharat B Aggarwal |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-03 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 9 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-11 Completed Date: 2010-11-26 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 2196-207 Citation Subset: IM |
Copyright Information:
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(c) 2010 AACR. |
Affiliation:
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Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Cell Line, Tumor Cell Membrane / drug effects, metabolism Cell Survival / drug effects Chromans / pharmacology* Colonic Neoplasms / genetics, pathology Down-Regulation / drug effects Extracellular Signal-Regulated MAP Kinases / metabolism* Humans Reactive Oxygen Species / metabolism* Receptors, Death Domain / genetics*, metabolism TNF-Related Apoptosis-Inducing Ligand / pharmacology* Tumor Suppressor Protein p53 / metabolism* Up-Regulation / drug effects Vitamin E / analogs & derivatives*, pharmacology bcl-2-Associated X Protein / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Chromans; 0/Reactive Oxygen Species; 0/Receptors, Death Domain; 0/TNF-Related Apoptosis-Inducing Ligand; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein; 1406-18-4/Vitamin E; 4382-43-8/plastochromanol 8; 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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