Abstract
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)γ in breast cancer cells. We ascertained that PPARγ mediates the inhibition of cycle progression in MCF7 cells exerted by the specific PPARγ agonist rosiglitazone [BRL4653 (BRL)], because this response was no longer notable in the presence of the receptor antagonist GW9662. We also provided evidence that BRL is able to up-regulate mRNA and protein levels of the tumor suppressor gene p53 and its effector p21WAF1/Cip1 in a time- and dose-dependent manner. Moreover, in transfection experiments with deletion mutants of the p53 gene promoter, we documented that the nuclear factor-κB sequence is required for the transcriptional response to BRL. Interestingly, EMSA showed that PPARγ binds directly to the nuclear factor-κB site located in the promoter region of p53, and chromatin immunoprecipitation experiments demonstrated that BRL increases the recruitment of PPARγ on the p53 promoter sequence. Next, both PPARγ and p53 were involved in the cleavage of caspases-9 and DNA fragmentation induced by BRL, given that GW9662 and an expression vector for p53 antisense blunted these effects. Our findings provide evidence that the PPARγ agonist BRL promotes the growth arrest and apoptosis in MCF7 cells, at least in part, through a cross talk between p53 and PPARγ, which may be considered an additional target for novel therapeutic interventions in breast cancer patients.
Estrogen Up-Regulation of p53 Gene Expression in MCF-7 Breast Cancer Cells Is Mediated by Calmodulin Kinase IV-Dependent Activation of a Nuclear Factor κB/CCAAT-Binding Transcription Factor-1 Complex