| Fenofibrate antagonizes Chk2 activation by inducing Wip1 expression: implications for cell proliferation and tumorigenesis. | |
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MedLine Citation:
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PMID: 20226795 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIMS: Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist that has been widely used to treat dyslipidemia. Previous studies have suggested that fenofibrate plays a role in cell proliferation and the development of hepatocarcinoma, but the underlying mechanism has not been fully characterized. In this report, we investigated whether fenofibrate treatment affected on the machinery of cell cycle checkpoint using nocodazole-induced cell cycle arrest. MAIN METHODS: The human normal liver cell line, CCL13 cells were treated with nocodazole and fenofibrate. Flow cytometry was performed for cell cycle analysis, and checkpoint kinase 2 (Chk2) and phosphatase Wip1 were analyzed by Western blot. KEY FINDINGS: Fenofibrate treatment overrode nocodazole-induced G2/M cell cycle arrest in a PPARalpha-independent manner. Mechanistically, fenofibrate treatment inhibited phosphorylation of checkpoint kinase Chk2 induced by nocodazole, and increased the expression of Wip1, a negative regulator of Chk2, suggesting that fenofibrate suppressed the nocodazole-induced G2/M cell cycle checkpoint through Wip1-mediated inhibition of Chk2 activation. SIGNIFICANCE: These results reveal a novel role of fenofibrate in cell cycle checkpoint control and provide a possible mechanistic explanation for how fenofibrate promotes cell proliferation and carcinogenesis. |
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Authors:
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Yeonsoo Joe; Mi-Hyang Do; Eunhui Seo; Soojeong Kang; Hwan-Tae Park; Jeanho Yun; Hye-Jeong Lee |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-11 |
Journal Detail:
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Title: Life sciences Volume: 86 ISSN: 1879-0631 ISO Abbreviation: Life Sci. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-04-23 Completed Date: 2010-05-06 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 0375521 Medline TA: Life Sci Country: Netherlands |
Other Details:
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Languages: eng Pagination: 716-21 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Pharmacology, Medical Sciences Research Center, Dong-A University College of Medicine, Busan, South Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Blotting, Western Cell Division / drug effects Cell Line Cell Proliferation / drug effects* Fenofibrate / pharmacology* Flow Cytometry G2 Phase / drug effects Humans Hypolipidemic Agents / pharmacology* Nocodazole / pharmacology PPAR alpha / agonists Phosphoprotein Phosphatases / genetics*, metabolism Phosphorylation / drug effects Protein-Serine-Threonine Kinases / antagonists & inhibitors* |
| Chemical | |
Reg. No./Substance:
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0/Hypolipidemic Agents; 0/PPAR alpha; 31430-18-9/Nocodazole; 49562-28-9/Fenofibrate; EC 2.7.1.11/checkpoint kinase 2; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.1.3.16/Phosphoprotein Phosphatases; EC 3.1.3.16/protein phosphatase 2C |
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