| Gossypol induces death receptor-5 through activation of the ROS-ERK-CHOP pathway and sensitizes colon cancer cells to TRAIL. | |
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MedLine Citation:
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PMID: 20837473 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Development of resistance to TRAIL, an apoptosis-inducing cytokine, is one of the major problems in its development for cancer treatment. Thus, pharmacological agents that are safe and can sensitize the tumor cells to TRAIL are urgently needed. We investigated whether gossypol, a BH3 mimetic that is currently in the clinic, can potentiate TRAIL-induced apoptosis. Intracellular esterase activity, sub-G(1) cell cycle arrest, and caspase-8, -9, and -3 activity assays revealed that gossypol potentiated TRAIL-induced apoptosis in human colon cancer cells. Gossypol also down-regulated cell survival proteins (Bcl-x(L), Bcl-2, survivin, XIAP, and cFLIP) and dramatically up-regulated TRAIL death receptor (DR)-5 expression but had no effect on DR4 and decoy receptors. Gossypol-induced receptor induction was not cell type-specific, as DR5 induction was observed in other cell types. Deletion of DR5 by siRNA significantly reduced the apoptosis induced by TRAIL and gossypol. Gossypol induction of the death receptor required the induction of CHOP, and thus, gene silencing of CHOP abolished gossypol-induced DR5 expression and associated potentiation of apoptosis. ERK1/2 (but not p38 MAPK or JNK) activation was also required for gossypol-induced TRAIL receptor induction; gene silencing of ERK abolished both DR5 induction and potentiation of apoptosis by TRAIL. We also found that reactive oxygen species produced by gossypol treatment was critical for TRAIL receptor induction and apoptosis potentiation. Overall, our results show that gossypol enhances TRAIL-induced apoptosis through the down-regulation of cell survival proteins and the up-regulation of TRAIL death receptors through the ROS-ERK-CHOP-DR5 pathway. |
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Authors:
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Bokyung Sung; Jayaraj Ravindran; Sahdeo Prasad; Manoj K Pandey; 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: 2010-09-13 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-08 Completed Date: 2011-02-09 Revised Date: 2011-11-14 |
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: 35418-27 Citation Subset: IM |
Affiliation:
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Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD 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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Apoptosis
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drug effects Apoptosis Regulatory Proteins / metabolism Blotting, Western Cell Line, Tumor Cell Survival / drug effects Colonic Neoplasms / genetics, metabolism, pathology Down-Regulation / drug effects Flow Cytometry Gossypol / pharmacology* HCT116 Cells Hela Cells Humans Mitogen-Activated Protein Kinase 1 / genetics, metabolism Mitogen-Activated Protein Kinase 3 / genetics, metabolism RNA Interference Reactive Oxygen Species / metabolism Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics, metabolism* Signal Transduction / drug effects* TNF-Related Apoptosis-Inducing Ligand / pharmacology* Transcription Factor CHOP / genetics, metabolism Up-Regulation / drug effects |
| Grant Support | |
ID/Acronym/Agency:
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CA-124787-01A2/CA/NCI NIH HHS; CA-16672/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Apoptosis Regulatory Proteins; 0/Reactive Oxygen Species; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/TNF-Related Apoptosis-Inducing Ligand; 147336-12-7/Transcription Factor CHOP; 303-45-7/Gossypol; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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