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

• Published in: British journal of pharmacology Vol. 143; no. 8; pp. 933 - 937
• Main Authors: Seargent, Jill M, Yates, Elisabeth A, Gill, Jason H
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2004; Nature Publishing
• Subjects: Biological and medical sciences; Breast cancer; GW9662; Medical sciences; peroxisome proliferator‐activated receptor (PPAR); Pharmacology. Drug treatments; PPARγ; rosiglitazone; Special Reports; Antineoplastic agent; Agonist; GW9662; Breast tumor; Thiazolidinedione derivatives; Breast cancer; Malignant tumor; PPARγ; peroxisome proliferator-activated receptor (PPAR); Mammary gland diseases; Hypoglycemic agent; Rosiglitazone; Antagonist; Tumor cell; Peroxisome proliferator activated receptor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705973

Peroxisome proliferator‐activated receptor gamma (PPARγ), 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 PPARγ signalling is now believed to be a strategy for treatment of several cancers, including breast. Although differential expression of PPARγ is observed in tumours compared to normal tissues and PPARγ 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 PPARγ antagonist GW9662 prevented activation of PPARγ and inhibited growth of human mammary tumour cell lines. Controversially, GW9662 prevented rosiglitazone‐mediated PPARγ activation, but enhanced rather than reversed rosiglitazone‐induced growth inhibition. As such, these data support the existence of PPARγ‐independent pathways and question the central belief that PPARγ ligands mediate their anticancer effects via activation of PPARγ. British Journal of Pharmacology (2004) 143, 933–937. doi:10.1038/sj.bjp.0705973