Selective activation of PPARγ in breast, colon, and lung cancer cell lines

Peroxisome proliferator-activated receptor gamma (PPARγ) plays a critical albeit poorly defined role in the development and progression of several cancer types including those of the breast, colon, and lung. A PPAR response element (PPRE) reporter assay was utilized to evaluate the selective transactivation of PPARγ in 10 different cell lines including normal mammary epithelial, breast, lung, and colon cancer cells. Cells were treated with one of four compounds including rosglitizone (Ros), ciglitizone (Cig), 15-deoxy-Δ^12,14-prostaglandin J₂ (PGJ₂), or GW 9662 (GW). We observed differences in transactivation between cell lines from different tissue origin, across cell lines from a single tissue type, and selective modulation of PPARγ within a single cell line by different ligands. Interestingly, GW, a PPARγ antagonist in adipocytes, enhanced PPRE reporter activation in normal mammary epithelial cells while it had virtually no effect in any of the cancer cell lines tested. Within each cancer type, individual cell lines were found to respond differently to distinct PPARγ ligands. For instance, Ros, Cig, and PGJ₂ were all potent agonist of PPARγ transactivation in lung adenocarcinoma cell lines while these same ligands had no effect in squamous cell or large cell carcinomas of the lung. Message levels of PPARγ and retinoid X receptor alpha (RXRα) in the individual cell lines were quantitated by real time-polymerase chain reaction (RT-PCR). The ratio of PPARγ to RXRα was predictive of how cells responded to co-treatment of Ros and 9-cis-retinoic acid, an RXRα agonist, in two out of three cell lines tested. These data indicate that PPARγ can be selectively modulated and suggests that it may be used as a therapeutic target for individual tumors.