Peroxisome proliferator-activated receptor-gamma ligands inhibit alpha5 integrin gene transcription in non-small cell lung carcinoma cells

Abstract

We previously showed that fibronectin stimulates the growth of non-small cell lung carcinoma (NSCLC) cells through integrin alpha5beta1-dependent signals. We also demonstrated that peroxisome proliferator-activated receptor (PPAR)gamma ligands inhibit lung carcinoma cell growth. Because alpha5beta1 activation elicits cellular signals linked to cell survival and regulation of cell cycle progression, we studied the effects of PPARgamma ligands on its expression. We found that PPARgamma ligands decreased mRNA and protein expression of the alpha5 subunit of the alpha5beta1 heterodimer in NSCLC; this was associated with reduced NSCLC adhesion to fibronectin. The suppressive effect of the PPARgamma ligands BRL 49653 and GW1929, but not PGJ(2), on alpha5 gene expression were reversed by GW9662, an antagonist of PPARgamma. GW1929 activated the extracellular regulated kinase (Erk), and an inhibitor of the Erk pathway (PD98095) prevented its effect on alpha5. PPARgamma ligands also reduced alpha5 gene promoter activity, and this was blocked by Erk antisense oligonucleotides. PPARgamma 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 PPARgamma ligands inhibit alpha5 expression in NSCLC through Erk-related signals.