Peroxisome proliferator-activated receptor-gamma activates p53 gene promoter binding to the nuclear factor-kappaB sequence in human MCF7 breast cancer cells

The aim of the present study was to provide newmechanistic insight into the growth arrest and apoptosiselicited by peroxisome proliferator-activatedreceptor (PPAR) in breast cancer cells. We ascertained that PPARgamma mediates the inhibition of cycle progression in MCF7 cells exerted by the specific PPARgamma 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 isable 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 withdeletion mutants of the p53 gene promoter, we documented that the nuclear factor-B sequence is required for the transcriptional response to BRL. Interestingly, EMSA showed that PPAR binds directly to the nuclear factor-B site located in thepromoter region of p53, and chromatin immunoprecipitationexperiments demonstrated that BRL increases the recruitment of PPAR on the p53 promoter sequence. Next, both PPARgamma 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 provideevidence that the PPAR agonist BRL promotes the growth arrest and apoptosis in MCF7 cells, at least in part, through a cross talk between p53 and PPARgamma, which may be considered an additional target for novel therapeutic interventions in breast cancer patients.