| Complementary cell-based high-throughput screens identify novel modulators of the unfolded protein response. | |
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MedLine Citation:
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PMID: 21844328 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Despite advances toward understanding the prevention and treatment of many cancers, patients who suffer from oral squamous cell carcinoma (OSCC) confront a survival rate that has remained unimproved for more than 2 decades, indicating our ability to treat them pharmacologically has reached a plateau. In an ongoing effort to improve the clinical outlook for this disease, we previously reported that an essential component of the mechanism by which the proteasome inhibitor bortezomib (PS-341, Velcade) induced apoptosis in OSCC required the activation of a terminal unfolded protein response (UPR). Predicated on these studies, the authors hypothesized that high-throughput screening (HTS) of large diverse chemical libraries might identify more potent or selective small-molecule activators of the apoptotic arm of the UPR to control or kill OSCC. They have developed complementary cell-based assays using stably transfected CHO-K1 cell lines that individually assess the PERK/eIF2α/CHOP (apoptotic) or the IRE1/XBP1 (adaptive) UPR subpathways. An 66 K compound collection was screened at the University of Michigan Center for Chemical Genomics that included a unique library of prefractionated natural product extracts. The mycotoxin methoxycitrinin was isolated from a natural extract and found to selectively activate the CHOP-luciferase reporter at 80 µM. A series of citrinin derivatives was isolated from these extracts, including a unique congener that has not been previously described. In an effort to identify more potent compounds, the authors examined the ability of citrinin and the structurally related mycotoxins ochratoxin A and patulin to activate the UPR. Strikingly, it was found that patulin at 2.5 to 10 µM induced a terminal UPR in a panel of OSCC cells that was characterized by an increase in CHOP, GADD34, and ATF3 gene expression and XBP1 splicing. A luminescent caspase assay and the induction of several BH3-only genes indicated that patulin could induce apoptosis in OSCC cells. These data support the use of this complementary HTS strategy to identify novel modulators of UPR signaling and tumor cell death. |
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Authors:
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Andrew M Fribley; Patricia G Cruz; Justin R Miller; Michael U Callaghan; Peter Cai; Neha Narula; Richard R Neubig; Hollis D Showalter; Scott D Larsen; Paul D Kirchhoff; Martha J Larsen; Douglas A Burr; Pamela J Schultz; Renju R Jacobs; Giselle Tamayo-Castillo; David Ron; David H Sherman; Randal J Kaufman |
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Publication Detail:
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Type: Journal Article Date: 2011-08-15 |
Journal Detail:
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Title: Journal of biomolecular screening Volume: 16 ISSN: 1552-454X ISO Abbreviation: J Biomol Screen Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-09-12 Completed Date: 2012-01-10 Revised Date: 2012-05-15 |
Medline Journal Info:
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Nlm Unique ID: 9612112 Medline TA: J Biomol Screen Country: United States |
Other Details:
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Languages: eng Pagination: 825-35 Citation Subset: IM |
Affiliation:
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Carmen and Ann Adams Department of Pediatrics, Division of Hematology/Oncology, Wayne State University, 421 E. Canfield, Detroit, MI 48201, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / pharmacology* Apoptosis Boronic Acids / pharmacology CHO Cells Carcinoma, Squamous Cell / drug therapy*, pathology Caspases / genetics, metabolism Cell Proliferation / drug effects Cricetinae Drug Evaluation, Preclinical / methods* Eukaryotic Initiation Factor-2 / genetics, metabolism Genes, Reporter High-Throughput Screening Assays* Humans Luciferases / analysis Mouth Neoplasms / drug therapy*, pathology Mycotoxins / pharmacology* Pyrazines / pharmacology Signal Transduction Transcription Factor CHOP / genetics, metabolism Transduction, Genetic Unfolded Protein Response / drug effects eIF-2 Kinase / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK088227-04/DK/NIDDK NIH HHS; R01 HL052173/HL/NHLBI NIH HHS; U01 TW007404-08/TW/FIC NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Boronic Acids; 0/Eukaryotic Initiation Factor-2; 0/Mycotoxins; 0/Pyrazines; 0/bortezomib; 147336-12-7/Transcription Factor CHOP; EC 1.13.12.-/Luciferases; EC 2.7.10.-/PERK kinase; EC 2.7.11.1/eIF-2 Kinase; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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