Combined Low Doses of PPARγ and RXR Ligands Trigger an Intrinsic Apoptotic Pathway in Human Breast Cancer Cells

被引:78
作者
Bonofiglio, Daniela [2 ]
Cione, Erika [2 ]
Qi, Hongyan [2 ]
Pingitore, Attilio [2 ]
Perri, Mariarita [2 ]
Catalano, Stefania [2 ]
Vizza, Donatella [2 ]
Panno, Maria Luisa [3 ]
Genchi, Giuseppe [2 ]
Fuqua, Suzanne A. W. [5 ]
Ando, Sebastiano [1 ,3 ,4 ]
机构
[1] Univ Calabria, Fac Pharm Nutr & Hlth Sci, I-87036 Cosenza, Italy
[2] Univ Calabria, Dept Pharmacobiol, I-87036 Cosenza, Italy
[3] Univ Calabria, Dept Cellular Biol, I-87036 Cosenza, Italy
[4] Univ Calabria, Ctr Sanit, I-87036 Cosenza, Italy
[5] Baylor Coll Med, Dept Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA
关键词
ACTIVATED-RECEPTOR-GAMMA; RETINOID-X-RECEPTOR; FACTOR-KAPPA-B; SELECTIVE RETINOIDS; INDUCE APOPTOSIS; THYROID-HORMONE; GROWTH; ACID; DIFFERENTIATION; EXPRESSION;
D O I
10.2353/ajpath.2009.081078
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Ligand activation of peroxisome proliferator-activated receptor (PPAR)gamma and retinoid X receptor (RXR) induces antitumor effects in cancer. We evaluated the ability of combined treatment with nanomolar levels of the PPAR gamma ligand rosiglitazone (BRL) and the RXR ligand 9-cis-retinoic acid (9RA) to promote antiproliferative effects in breast cancer cells. BRL and 9RA in combination strongly inhibit of cell viability in MCF-7, MCF-7TR1, SKBR-3, and T-47D breast cancer cells, whereas MCF-10 normal breast epithelial cells are unaffected. In MCF-7 cells, combined treatment with BRL and 9RA up-regulated mRNA and protein levels of both the tumor suppressor P53 and its effector p21(WAF1/Cip1). Functional experiments indicate that the nuclear factor-kappa B site in the p53 promoter is required for the transcriptional response to BRL plus 9RA. We observed that the intrinsic apoptotic pathway in MCF-7 cells displays an ordinated sequence of events, including disruption of mitochondrial membrane potential, release of cytochrome c, strong caspase 9 activation, and, finally, DNA fragmentation. An expression vector for p53 antisense abrogated the biological effect of both ligands, which implicates involvement of P53 in PPAR gamma/RXR-dependent activity in all of the human breast malignant cell lines tested. Taken together, our results suggest that multidrug regimens including a combination of PPAR gamma and RXR ligands may provide a therapeutic advantage in breast cancer treatment. (Am J Pathol 2009, 175:1270-1280, DOI: 10.2353/ajpath.2009.081078)
引用
收藏
页码:1270 / 1280
页数:11
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