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Submitted on May 8, 2006
Accepted on July 26, 2006
Dept. Pharmaco-Biology, Dept. Cellular Biology, Faculty of Pharmacy University of Calabria 87030 Arcavacata di Rende (CS) Italy
* To whom correspondence should be addressed. E-mail: sebastiano.ando{at}unical.it.
The aim of the present study was to provide new mechanistic insight into the growth arrest and apoptosis elicited by Peroxisome proliferator-activated receptor (PPAR) 
in breast cancer cells. We ascertained that PPAR mediates the inhibition of cycle progression in MCF7 cells exerted by the specific PPAR agonist rosiglitazone (BRL), since this response was no longer notable in presence of the receptor antagonist GW9662 (GW). We also evidenced that BRL is able to up-regulate in a time- and dose-dependent manner mRNA and protein levels of the tumor suppressor gene p53 and its effector p21WAF1/Cip1. Moreover, in transfection experiments with deletion mutants of the p53 gene promoter, we documented that the Nuclear Factor kB (NFkB) sequence is required for the transcriptional response to BRL. Interestingly, electrophoretic mobility shift assay showed that PPAR binds directly to the NFkB site located in the promoter region of p53 and chromatin immunoprecipitation experiments demonstrated that BRL increases the recruitment of PPAR on the p53 promoter sequence. Next, both PPAR and p53 were involved in the cleavage of caspases-9 and DNA fragmentation induced by BRL, given that GW and an expression vector for p53 antisense blunted these effects. Our findings evidenced that the PPAR agonist BRL promotes the growth arrest and apoptosis in MCF7 cells, at least in part, through a crosstalk between p53 and PPAR which may be considered an additional target for novel therapeutic interventions in breast cancer patients.
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p53 •
p21WAF1/Cip1 •
breast cancer cells •
rosiglitazone
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