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We previously showed that fibronectin stimulates the growth of non-small cell lung carcinoma (NSCLC) cells through integrin α5β1-dependent signals. We also demonstrated that peroxisome proliferator-activated receptor (PPAR)γ ligands inhibit lung carcinoma cell growth. Because α5β1 activation elicits cellular signals linked to cell survival and regulation of cell cycle progression, we studied the effects of PPARγ ligands on its expression. We found that PPARγ ligands decreased mRNA and protein expression of the α5 subunit of the α5β1 heterodimer in NSCLC; this was associated with reduced NSCLC adhesion to fibronectin. The suppressive effect of the PPARγ ligands BRL 49653 and GW1929, but not PGJ2, on α5 gene expression were reversed by GW9662, an antagonist of PPARγ. GW1929 activated the extracellular regulated kinase (Erk), and an inhibitor of the Erk pathway (PD98095) prevented its effect on α5. PPARγ ligands also reduced α5 gene promoter activity, and this was blocked by Erk antisense oligonucleotides. PPARγ ligands GW1929 and BRL49653 inhibited AP-1 DNA binding, whereas 15d-PGJ2 inhibited Sp1 DNA binding; both effects were blocked by Erk antisense oligonucleotides. GW1929 partially blocked fibronectin-induced NSCLC cell growth, but did not affect cell growth induced by epidermal growth factor. These results suggest that PPARγ ligands inhibit α5 expression in NSCLC through Erk-related signals.