Peroxisome proliferator-activated receptor-γ ligands inhibit α5 integrin gene transcription in non-small cell lung carcinoma cells

We previously showed that fibronectin stimulates the growth of non-small cell lung carcinoma (NSCLC) cells through integrin alpha 5 beta 1-dependent signals. We also demonstrated that peroxisome proliferator-activated receptor (PPAR)gamma ligands inhibit lung carcinoma cell growth. Because alpha 5 beta 1 activation elicits cellular signals linked to cell survival and regulation of cell cycle progression, we studied the effects of PPAR gamma ligands on its expression. We found that PPAR gamma ligands decreased mRNA and protein expression of the alpha 5 subunit of the alpha 5 beta 1 heterodimer in NSCLC; this was associated with reduced NSCLC adhesion to fibronectin. The suppressive effect of the PPAR gamma ligands BRL 49653 and GW1929, but not PGJ(2), on alpha 5 gene expression were reversed by GW9662, an antagonist of PPAR gamma. GW1929 activated the extracellular regulated kinase (Erk), and an inhibitor of the Erk pathway (PD98095) prevented its effect on a5. PPAR gamma ligands also reduced alpha 5 gene promoter activity, and this was blocked by Erk antisense oligonucleotides. PPAR gamma ligands GW1929 and BRL49653 inhibited AP-1 DNA binding, whereas 15d-PGJ(2) 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 PPAR gamma ligands inhibit a5 expression in NSCLC through Erk-related signals.