Document Detail


Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell growth.
MedLine Citation:
PMID:  20060890     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Sustained activation of Akt kinase acts as a focal regulator to increase cell growth and survival, which causes tumorigenesis including breast cancer. Statins, potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, display anticancer activity. The molecular mechanisms by which statins block cancer cell growth are poorly understood. We demonstrate that in the tumors derived from MDA-MB-231 human breast cancer cell xenografts, simvastatin significantly inhibited phosphorylation of Akt with concomitant attenuation of the expression of the anti-apoptotic protein Bcl(XL). In many cancer cells, Bcl(XL) is a target of NFkappaB. Simvastatin inhibited the DNA binding and transcriptional activities of NFkappaB resulting in marked reduction in transcription of Bcl(XL). Signals transmitted by anti-neoplastic mechanism implanted in the cancer cells serve to obstruct the initial outgrowth of tumors. One such mechanism represents the action of the tumor suppressor protein PTEN, which negatively regulates Akt kinase activity. We provide the first evidence for significantly increased levels of PTEN in the tumors of simvastatin-administered mice. Importantly, simvastatin markedly prevented binding of NFkappaB to the two canonical recognition elements, NFRE-1 and NFRE-2 present in the PTEN promoter. Contrary to the transcriptional suppression of Bcl(XL), simvastatin significantly increased the transcription of PTEN. Furthermore, expression of NFkappaB p65 subunit inhibited transcription of PTEN, resulting in reduced protein expression, which leads to enhanced phosphorylation of Akt. Taken together, our data present a novel bifaceted mechanism where simvastatin acts on a nodal transcription factor NFkappaB, which attenuates the expression of anti-apoptotic Bcl(XL) and simultaneously derepresses the expression of anti-proliferative/proapoptotic tumor suppressor PTEN to prevent breast cancer cell growth.
Authors:
Nayana Ghosh-Choudhury; Chandi Charan Mandal; Nandini Ghosh-Choudhury; Goutam Ghosh Choudhury
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-01-11
Journal Detail:
Title:  Cellular signalling     Volume:  22     ISSN:  1873-3913     ISO Abbreviation:  Cell. Signal.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-02-22     Completed Date:  2010-05-05     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  8904683     Medline TA:  Cell Signal     Country:  England    
Other Details:
Languages:  eng     Pagination:  749-58     Citation Subset:  IM    
Copyright Information:
Published by Elsevier Inc.
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MeSH Terms
Descriptor/Qualifier:
Animals
Breast Neoplasms / enzymology*,  pathology*
Cell Line, Tumor
Cell Proliferation / drug effects
Enzyme Activation / drug effects
Female
Humans
Mice
NF-kappa B / metabolism*
PTEN Phosphohydrolase / genetics*,  metabolism
Phosphorylation / drug effects
Protein Binding / drug effects
Proto-Oncogene Proteins c-akt / metabolism
Response Elements / genetics
Simvastatin / pharmacology*
Transcription, Genetic / drug effects
Xenograft Model Antitumor Assays
bcl-X Protein / genetics
Grant Support
ID/Acronym/Agency:
R01 AR052425-04/AR/NIAMS NIH HHS; R01 AR052425-05/AR/NIAMS NIH HHS; R01 AR52425/AR/NIAMS NIH HHS; R01 DK050190/DK/NIDDK NIH HHS; R01 DK050190-09/DK/NIDDK NIH HHS; R01 DK50190/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/NF-kappa B; 0/bcl-X Protein; AGG2FN16EV/Simvastatin; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase
Comments/Corrections

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