| ERK1/2 deactivation enhances cytoplasmic Nur77 expression level and improves the apoptotic effect of fenretinide in human liver cancer cells. | |
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MedLine Citation:
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PMID: 21241664 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Fenretinide, a synthetic retinoid, is a promising anticancer agent based on many in vitro, animal, and chemoprevention clinical trial studies. However, cells such as HepG2 human liver cancer cells are resistant to the apoptotic effect of fenretinide. Previously, we have shown that fenretinide-induced apoptosis is Nur77 dependent, and the sensitivity of the cancer cells to fenretinide-induced apoptosis is positively associated with cytoplasmic enrichment of Nur77. The goal of current study was to identify means to modulate nuclear export of Nur77 in order to improve the efficacy of fenretinide. Fenretinide treatment deactivated ERK1/2 in Huh7 cells, but activated ERK1/2 in HepG2 cells, which was positively associated with the sensitivity of cells to the apoptotic effect of fenretinide. Neither fenretinide nor ERK1/2 inhibitor PD98059 alone could affect the survival of HepG2 cells, but the combination of both induced cell death and increased caspase 3/7 activity. In fenretinide sensitive Huh7 cells, activation of ERK1/2 by epidermal growth factor (EGF) prevented fenretinide-induced cell death and caspase 3/7 induction. In addition, modulation of ERK1/2 changed the intracellular localization of Nur77. Fenretinide/PD98059-induced cell death of HepG2 cell was positively associated with induction and cytoplasmic location as well as mitochondria enrichment of Nur77. The effect was specific for ERK1/2 because other mitogen activated protein kinases such as P38, Akt, and JNK did not have correlated changes in their phosphorylation levels. Taken together, the current study demonstrates that ERK1/2-modulated Nur77 intracellular location dictates the efficacy of fenretinide-induced apoptosis. |
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Authors:
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Hui Yang; Yuqiang Nie; Yuyuan Li; Yu-Jui Yvonne Wan |
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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: 2011-01-15 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 81 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-03-15 Completed Date: 2011-05-31 Revised Date: 2012-12-12 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 910-6 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Gastroenterology, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Apoptosis / drug effects* Blotting, Western Cell Line, Tumor Cytoplasm / drug effects*, metabolism Fenretinide / pharmacology* Humans Liver Neoplasms / enzymology, metabolism, pathology* Microscopy, Confocal Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*, metabolism Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*, metabolism Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA 53596/CA/NCI NIH HHS; P20 RR 021940/RR/NCRR NIH HHS; R01 CA053596/CA/NCI NIH HHS; R01 CA053596-21/CA/NCI NIH HHS; R01 CA053596-22/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/NR4A1 protein, human; 0/Nuclear Receptor Subfamily 4, Group A, Member 1; 65646-68-6/Fenretinide; EC 2.7.11.24/MAPK1 protein, human; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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