title: Bid as a potential target of apoptotic effects exerted by low doses of PPARγ and RXR ligands in breast cancer cells.
abstract: The combined treatment with nanomolar doses of the PPARγ 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 PPARγ 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 ligand 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, PPARγ 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 PPARγ and RXR ligands, address Bid as a potential target in the novel therapeutical strategies for breast cancer.
authors.affiliation: Department of Pharmaco-Biology, Centro Sanitario, Faculty of Pharmacy Nutritional and Health Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.forename: Erika
authors.initials: E
authors.lastname: Cione
authors.forename: Donatella
authors.initials: D
authors.lastname: Vizza
authors.forename: Mariarita
authors.initials: M
authors.lastname: Perri
authors.forename: Attilio
authors.initials: A
authors.lastname: Pingitore
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qi
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.forename: Daniela
authors.initials: D
authors.lastname: Rovito
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Genchi
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008024:Ligands; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D047488:Retinoid X Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; D008024:Ligands; D047495:PPAR gamma; D034741:RNA, Small Interfering; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; D016159:Tumor Suppressor Protein p53; D000077154:Rosiglitazone; D000077556:Alitretinoin; D014212:Tretinoin