| 4-O-carboxymethyl ascochlorin causes ER stress and induced autophagy in human hepatocellular carcinoma cells. | |
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MedLine Citation:
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PMID: 22433868 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The synthetic derivative of ascochlorin, 4-O-carboxymethyl ascochlorin (AS-6) is an agonist of the nuclear hormone receptor PPARγ and has been shown to induce differentiation in mouse pre-adipocytes and to ameliorate type II diabetes in a murine model. AS-6 was cytotoxic when added at micromolar concentrations to cultures of three different human cancer cell lines. We used gel electrophoresis and mass spectrometry to identify proteins with altered expression in human hepatocarcinoma cells (HepG2) cells after 12 h in the presence of AS-6 and found 58 proteins that were differentially expressed. Many of the proteins showing increased expression in cells treated with AS-6 are involved in protein quality control, including glucose-regulated protein 78 (GRP78/BiP), a regulator of ER stress responses, and the transcriptional regulator CHOP, which mediates ER stress-induced apoptosis. Cells treated with AS-6 undergo an autophagic response accompanied by increased expression of beclin1, ATG5, and LC3-II and autophagosome formation marked by the appearance of large vesicles containing LC3-II. Grp78 induction was inhibited when the PPARγ antagonist, GW9662, was added together with AS-6, and autophagy and cell death were partially blocked. 3-methyl-adenine (3-MA), an inhibitor of phosphatidyl inositol 3-kinase (PI3-kinase) prevented induction of ATG5 and activation of LC3-II and blocked autophagosome formation. 3-MA also blocked induction of GRP78 and CHOP, suggesting that PI3-kinase, which is known to mediate ER stress-induced autophagy, also plays a role in initiating apoptosis in response to ER stress. Together these data establish that the cytotoxicity of AS-6 operates by a mechanism dependent on ER stress-induced autophagy and apoptosis. |
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Authors:
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Jeong Han Kang; Young-Chae Chang; Michael R Maurizi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural Date: 2012-03-20 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-05-07 Completed Date: 2012-07-30 Revised Date: 2013-05-06 |
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: 15661-71 Citation Subset: IM |
Affiliation:
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Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis Regulatory Proteins
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genetics,
metabolism Autophagy / drug effects* Blotting, Western Carcinoma, Hepatocellular / genetics, metabolism, pathology Cell Line, Tumor Cell Survival / drug effects Dose-Response Relationship, Drug Electrophoresis, Gel, Two-Dimensional Endoplasmic Reticulum Stress / drug effects* Gene Expression / drug effects Glycolates / pharmacology* Hep G2 Cells Humans Liver Neoplasms / genetics, metabolism, pathology Membrane Proteins / genetics, metabolism Microscopy, Fluorescence Microtubule-Associated Proteins / genetics, metabolism Phagosomes / drug effects, metabolism Proteomics / methods RNA Interference Reverse Transcriptase Polymerase Chain Reaction Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Unfolded Protein Response / drug effects |
| Chemical | |
Reg. No./Substance:
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0/ATG5 protein, human; 0/Apoptosis Regulatory Proteins; 0/BECN1 protein, human; 0/Glycolates; 0/Membrane Proteins; 0/Microtubule-Associated Proteins; 0/light chain 3, human; 84435-25-6/4-O-carboxymethylascochlorin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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