Document Detail


Fenofibrate-induced nuclear translocation of FoxO3A triggers Bim-mediated apoptosis in glioblastoma cells in vitro.
MedLine Citation:
PMID:  22732497     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Anti-neoplastic potential of calorie restriction or ligand-induced activation of peroxisome proliferator activated receptors (PPARs) has been demonstrated in multiple studies; however, mechanism(s) by which tumor cells respond to these stimuli remain to be elucidated. One of the potent agonists of PPARα, fenofibrate, is a commonly used lipid-lowering drug with low systemic toxicity. Fenofibrate-induced PPARα transcriptional activity is expected to shift energy metabolism from glycolysis to fatty acid β-oxidation, which in the long-term, could target weak metabolic points of glycolysis-dependent glioblastoma cells. The results of this study demonstrate that 25 μM fenofibrate can effectively repress malignant growth of primary glial tumor cells and glioblastoma cell lines. This cytostatic action involves G(1) arrest accompanied by only a marginal level of apoptotic cell death. Although the cells treated with 25 μM fenofibrate remain arrested, the cells treated with 50 μM fenofibrate undergo massive apoptosis, which starts after 72 h of the treatment. This delayed apoptotic event was preceded by FoxO3A nuclear accumulation, FoxO3A phosphorylation on serine residue 413, its elevated transcriptional activity and expression of FoxO-dependent apoptotic protein, Bim. siRNA-mediated inhibition of FoxO3A attenuated fenofibrate-induced apoptosis, indicating a direct involvement of this transcription factor in the fenofibrate action against glioblastoma. These properties of fenofibrate, coupled with its low systemic toxicity, make it a good candidate in support of conventional therapies against glial tumors.
Authors:
Anna Wilk; Katarzyna Urbanska; Maja Grabacka; Jennifer Mullinax; Cezary Marcinkiewicz; David Impastato; John J Estrada; Krzysztof Reiss
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-25     Completed Date:  2012-11-26     Revised Date:  2013-07-16    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2660-71     Citation Subset:  IM    
Affiliation:
Neurological Cancer Research, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
Apoptosis Regulatory Proteins / metabolism*
Cell Line, Tumor
Cell Nucleolus / metabolism
Energy Metabolism
Fenofibrate / toxicity*
Forkhead Transcription Factors / antagonists & inhibitors,  genetics,  metabolism*
G1 Phase Cell Cycle Checkpoints / drug effects
Glioblastoma / metabolism,  pathology
Humans
Hypolipidemic Agents / toxicity*
Membrane Proteins / metabolism*
PPAR gamma / agonists,  metabolism
Phosphorylation
Proto-Oncogene Proteins / metabolism*
RNA Interference
RNA, Small Interfering / metabolism
Grant Support
ID/Acronym/Agency:
R01CA095518/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Bcl-2-like protein 11; 0/FOXO3 protein, human; 0/Forkhead Transcription Factors; 0/Hypolipidemic Agents; 0/Membrane Proteins; 0/PPAR gamma; 0/Proto-Oncogene Proteins; 0/RNA, Small Interfering; 49562-28-9/Fenofibrate
Comments/Corrections
Comment In:
Cell Cycle. 2012 Sep 1;11(17):3154   [PMID:  22895169 ]
Cell Cycle. 2012 Sep 15;11(18):3353   [PMID:  22918249 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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