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

Peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma in 10 different cell lines including normal mammary epithelia], breast, lung, and colon cancer cells. Cells were treated with one of four compounds including rosglitizone (Ros), ciglitizone (Cig), 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2)), 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 PPAR gamma within a single cell line by different ligands. Interestingly, GW, a PPAR gamma antagonist in adipocytes, enhanced PPRE reporter activation in normal mammary epithelia] 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 PPAR gamma ligands. For instance, Ros, Cig, and PGJ2 were all potent agonist of PPAR gamma transactivation in lung adenocarcinorna cell lines while these same ligands had no effect in squamous cell or large cell carcinomas of the lung. Message levels of PPAR gamma and retinoid X receptor alpha (RXR alpha) in the individual cell lines were quantitated by real time-polymerase chain reaction (RT-PCR). The ratio of PPAR gamma to RXRa was predictive of how cells responded to co-treatment of Ros and 9-cis-retinoic acid, an RXR alpha agonist, in two out of three cell lines tested. These data indicate that PPAR gamma can be selectively modulated and suggests that it may be used as a therapeutic target for individual tumors. (c) 2005 Elsevier Ireland Ltd. All rights reserved.