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Published ahead of print on January 27, 2005, doi:10.1165/rcmb.2004-0345OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 4, April 2005, 350-359

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Submitted on November 8, 2004
Revised on January 21, 2005

PPAR{gamma} ligands inhibit {alpha}5 integrin gene transcription in non-small cell lung carcinoma cells

ShouWei Han1, Hilda N Rivera2, and Jesse Roman3*

1 Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia, USA, 2 Department of Medicine, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA, 3 Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia, USA; Department of Medicine, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA

* To whom correspondence should be addressed. E-mail: jroman{at}emory.edu.

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 PPAR{gamma} ligands inhibit lung carcinoma cell growth. Since {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 PGJ2, 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 {alpha}5. 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; while 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{gamma} ligands inhibit {alpha}5 expression in NSCLC through Erk-related signals.




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