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Peroxisome Proliferator-Activated Receptor- Activates p53 Gene Promoter Binding to the Nuclear Factor-B Sequence in Human MCF7 Breast Cancer Cells

Department of Pharmaco-Biology (D.B., S.A., S.C., S.G., M.B., E.M., H.Q., C.M, M.M.), Department of Cellular Biology (M.G., S.A.), Faculty of Pharmacy (S.A.) University of Calabria, 87030 Arcavacata di Rende, (Cosenza) Italy

Address all correspondence and requests for reprints to: Professor Sebastiano Andò, Faculty of Pharmacy-University of Calabria, Arcavacata-Rende (Cosenza) 87036, Italy. E-mail: sebastiano.ando{at}unical.it or daniela.bonofiglio{at}tin.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 [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 p21^WAF1/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-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 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 GW9662 and an expression vector for p53 antisense blunted these effects. Our findings provide evidence 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 PPAR, which may be considered an additional target for novel therapeutic interventions in breast cancer patients.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ

Ligands:   GW 9662  |  Rosiglitazone

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