Document Detail


Evidence for activation of mutated p53 by apigenin in human pancreatic cancer.
MedLine Citation:
PMID:  22227579     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pancreatic cancer is an exceedingly lethal disease with a five-year survival that ranks among the lowest of gastrointestinal malignancies. Part of its lethality is attributable to a generally poor response to existing chemotherapeutic regimens. New therapeutic approaches are urgently needed. We aimed to elucidate the anti-neoplastic mechanisms of apigenin-an abundant, naturally-occurring plant flavonoid-with a particular focus on p53 function. Pancreatic cancer cells (BxPC-3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis with apigenin treatment. p53 post-translational modification, nuclear translocation, DNA binding, and upregulation of p21 and PUMA were all enhanced by apigenin treatment despite mutated p53 in both cell lines. Transcription-dependent p53 activity was reversed by pifithrin-α, a specific DNA binding inhibitor of p53, but not growth inhibition or apoptosis suggesting transcription-independent p53 activity. This was supported by immunoprecipitation assays which demonstrated disassociation of p53/BclXL and PUMA/BclXL and formation of complexes with Bak followed by cytochrome c release. Treated animals grew smaller tumors with increased cellular apoptosis than those fed control diet. These results suggest that despite deactivating mutation, p53 retains some of its function which is augmented following treatment with apigenin. Cell cycle arrest and apoptosis induction may be mediated by transcription-independent p53 function via interactions with BclXL and PUMA. Further study of flavonoids as chemotherapeutics is warranted.
Authors:
Jonathan C King; Qing-Yi Lu; Gang Li; Aune Moro; Hiroki Takahashi; Monica Chen; Vay Liang W Go; Howard A Reber; Guido Eibl; O Joe Hines
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Publication Detail:
Type:  Journal Article     Date:  2011-12-29
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1823     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-06     Completed Date:  2012-05-10     Revised Date:  2014-05-26    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  593-604     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier B.V. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apigenin / metabolism*,  pharmacology,  therapeutic use
Apoptosis / drug effects
Apoptosis Regulatory Proteins / genetics,  metabolism
Benzothiazoles / metabolism
Cell Line, Tumor
Dietary Supplements
Humans
Male
Mice
Mice, Nude
Mutation*
Neoplasms, Experimental / metabolism,  therapy
Pancreatic Neoplasms / drug therapy,  genetics,  metabolism*
Proto-Oncogene Proteins / genetics,  metabolism
Toluene / analogs & derivatives,  metabolism
Tumor Suppressor Protein p53 / antagonists & inhibitors,  genetics*,  metabolism*
bcl-X Protein / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
P01 AT003960/AT/NCCAM NIH HHS; P01 AT003960-05/AT/NCCAM NIH HHS; P01 CA163200/CA/NCI NIH HHS; R01 CA122042/CA/NCI NIH HHS; UL1 TR000124/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/BBC3 protein, human; 0/BCL2L1 protein, human; 0/Benzothiazoles; 0/Proto-Oncogene Proteins; 0/Tumor Suppressor Protein p53; 0/bcl-X Protein; 0/pifithrin; 3FPU23BG52/Toluene; 7V515PI7F6/Apigenin
Comments/Corrections

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