Peroxisome proliferator-activated receptor- ligands suppress fibronectin gene expression in human lung carcinoma cells: involvement of both CRE and Sp1

Han, ShouWei, Jeffrey D. Ritzenthaler, Hilda N. Rivera, and Jesse Roman. Peroxisome proliferator-activated receptorligands suppress fibronectin gene expression in human lung carcinoma cells: involvement of both CRE and Sp1. Am J Physiol Lung Cell Mol Physiol 289: L419–L428, 2005. First published May 20, 2005; doi:10.1152/ajplung.00002.2005.—Lung carcinoma often occurs in patients with chronic lung disease such as tobacco-related emphysema and asbestos-related pulmonary fibrosis. These diseases are characterized by dramatic alterations in the content and composition of the lung extracellular matrix, and we believe this “altered” matrix has the ability to promote lung carcinoma cell growth. One extracellular matrix molecule shown to be altered in these lung diseases is fibronectin (Fn). We previously reported increased growth and survival of non-small cell lung carcinoma (NSCLC) cells exposed to Fn. Thus Fn may serve as a mitogen/survival factor for NSCLC and therefore represents a novel target for anti-cancer strategies. To this end, we studied the effects of the PPAR ligands 15d-PGJ2, rosiglitazone (BRL49653), and troglitazone on Fn expression in NSCLC cells and found that they were able to inhibit Fn gene transcription. Inhibition of Fn expression by BRL49653 and troglitazone, but not by 15d-PGJ2, was prevented by the specific PPAR antagonist GW-9662 and by PPAR small interfering RNA. Working with Fn deletion and mutated promoter constructs, we found that the region between 170 and 50 bp downstream from the transcriptional start site of the promoter was involved in PPAR ligand inhibition. PPAR ligands also diminished the phosphorylation of CREB, diminished Sp1 nuclear protein expression, and prevented the binding of these transcription factors to CRE and Sp1 sites, respectively, within the Fn promoter. In summary, our results demonstrate that PPAR ligands inhibit Fn gene expression in NSCLC cells through PPAR -dependent and -independent pathways that affect both CREB and Sp1.