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Peroxisome Proliferator–Activated Receptor- Ligands Inhibit 5 Integrin Gene Transcription in Non–Small Cell Lung Carcinoma Cells

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine; and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to ShouWei Han, M.D., Ph.D., Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Whitehead Bioresearch Building, 615 Michael Street, Suite 205-M, Atlanta, GA 30322. E-mail: shan2{at}emory.edu

We previously showed that fibronectin stimulates the growth of non–small cell lung carcinoma (NSCLC) cells through integrin 5ß1–dependent signals. We also demonstrated that peroxisome proliferator–activated receptor (PPAR) ligands inhibit lung carcinoma cell growth. Because 5ß1 activation elicits cellular signals linked to cell survival and regulation of cell cycle progression, we studied the effects of PPAR ligands on its expression. We found that PPAR ligands decreased mRNA and protein expression of the 5 subunit of the 5ß1 heterodimer in NSCLC; this was associated with reduced NSCLC adhesion to fibronectin. The suppressive effect of the PPAR ligands BRL 49653 and GW1929, but not PGJ₂, on 5 gene expression were reversed by GW9662, an antagonist of PPAR. GW1929 activated the extracellular regulated kinase (Erk), and an inhibitor of the Erk pathway (PD98095) prevented its effect on 5. PPAR ligands also reduced 5 gene promoter activity, and this was blocked by Erk antisense oligonucleotides. PPAR ligands GW1929 and BRL49653inhibited 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 PPAR ligands inhibit 5 expression in NSCLC through Erk-related signals.

Key Words: 5 integrin • Erk • human lung carcinoma • PPAR • transcription factors

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