GW9662, a potent antagonist of PPARγ, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARγ agonist rosiglitazone, independently of PPARγ activation
- 1 December 2004
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 143 (8) , 933-937
- https://doi.org/10.1038/sj.bjp.0705973
Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is activated by several compounds, including the thiazolidinediones. In addition to being a therapeutic target for obesity, hypolipidaemia and diabetes, perturbation of PPARgamma signalling is now believed to be a strategy for treatment of several cancers, including breast. Although differential expression of PPARgamma is observed in tumours compared to normal tissues and PPARgamma agonists have been shown to inhibit tumour cell growth and survival, the interdependence of these observations is unclear. This study demonstrated that the potent, irreversible and selective PPARgamma antagonist GW9662 prevented activation of PPARgamma and inhibited growth of human mammary tumour cell lines. Controversially, GW9662 prevented rosiglitazone-mediated PPARgamma activation, but enhanced rather than reversed rosiglitazone-induced growth inhibition. As such, these data support the existence of PPARgamma-independent pathways and question the central belief that PPARgamma ligands mediate their anticancer effects via activation of PPARgamma.Keywords
This publication has 19 references indexed in Scilit:
- Multiple Transcription Factor Profiling by Enzyme-Linked ImmunoassayBioTechniques, 2002
- Functional Consequences of Cysteine Modification in the Ligand Binding Sites of Peroxisome Proliferator Activated Receptors by GW9662Biochemistry, 2002
- Faculty Opinions recommendation of Anticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor gamma and mediated by inhibition of translation initiation.Published by H1 Connect ,2001
- Magnitude of Peroxisome Proliferator-Activated Receptor-γ Activation is Associated with Important and Seemingly opposite Biological Responses in Breast Cancer CellsJournal of Investigative Medicine, 2001
- Troglitazone Inhibits Growth of MCF-7 Breast Carcinoma Cells by Targeting G1 Cell Cycle RegulatorsBiochemical and Biophysical Research Communications, 2001
- Therapeutic treatment of DMBA-induced mammary tumors with PPAR ligands.2001
- Peroxisome Proliferator-Activated Receptors: From Genes to PhysiologyRecent Progress in Hormone Research, 2001
- Induction of adipocyte-specific gene expression is correlated with mammary tumor regression by the retinoid X receptor-ligand LGD1069 (targretin).2000
- Peroxisome proliferator-activated receptor gamma ligands inhibit estrogen biosynthesis in human breast adipose tissue: possible implications for breast cancer therapy.2000
- Ligands for peroxisome proliferator-activated receptorγ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX miceProceedings of the National Academy of Sciences, 1998