Journal
CELL CYCLE
Volume 10, Issue 14, Pages 2344-2354Publisher
LANDES BIOSCIENCE
DOI: 10.4161/cc.10.14.15917
Keywords
PPAR gamma; RXR; apoptosis; mitochondria; bid; breast cancer
Categories
Funding
- AIRC
- Foundation Lilli Funaro
- MURST
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The combined treatment with nanomolar doses of the PPAR gamma ligand Rosiglitazone (BRL) and the RXR ligand 9-cis-retinoic acid (9RA) induces a p53-dependent apoptosis in MCF7, SKBR3 and T47D human breast cancer cells. Since MCF7 cells express a wild type p53 protein, while SKBR3 and T47D cells harbor endogenous mutant p53, we elucidated the mechanism through which PPAR gamma and RXR ligands triggered apoptotic processes independently of p53 transcriptional activity. We showed an upregulation of Bid expression enhancing the association between Bid/p53 in both cytosol and mitochondria after the ligands treatment. Particularly, in the mitochondria the complex involves the truncated Bid that plays a key role in the apoptotic process induced by BRL and 9RA since the disruption of mitochondrial membrane potential, the induction of PARP cleavage and the percentage of TUNEL-positive cells were reversed after knocking down Bid. Moreover, PPAR gamma and RXR ligands were able to reduce mitochondrial GST activity, which was no longer noticeable silencing Bid expression, suggesting the potential of Bid in the regulation of mitochondrial intracellular reactive oxygen species scavenger activity. Our data, providing new insight into the role of p53/Bid complex at the mitochondria in promoting breast cancer cell apoptosis upon low doses of PPAR gamma and RXR ligands, address Bid as a potential target in the novel therapeutical strategies for breast cancer.
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