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J. Biol. Chem., Vol. 282, Issue 11, 7961-7972, March 16, 2007

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Extracellular Matrix Fibronectin Increases Prostaglandin E₂ Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

THE ROLE OF AP-2^*

ShouWei Han¹, Jeffrey D. Ritzenthaler, Byron Wingerd, Hilda N. Rivera^¶, and Jesse Roman^¶

From the Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, the Department of Biochemistry, Michigan State University, East Lansing, Michigan 48824, and the ^¶Atlanta Veterans Affairs Medical Center, Atlanta, Georgia 30033

We have previously demonstrated that fibronectin (Fn) stimulates the proliferation of non-small cell lung carcinoma (NSCLC) cell growth through the induction of cyclooxygenase-2 (COX-2) and prostaglandin E₂ secretion. Here, we demonstrate that NSCLC cells express mRNA and protein for the prostaglandin E₂ receptor EP4 and that Fn enhances its stimulatory effect by inducing the expression of EP4, but not of EP1, EP2, and EP3 receptor subtypes. The effect of Fn on EP4 was inhibited by an antibody against 51 integrin and by inhibitors of phosphoinositide 3-kinase (wortmannin) and extracellular signal-regulated kinase (PD98095), but not by inhibitors of protein kinase C (calphostin C), of protein kinase A (H-89), or of mammalian target of rapamycin (rapamycin). A COX-2 small interfering RNA was also inhibitory. Fn significantly increased AP-2 binding activity in the promoter of the EP4 gene, and AP-2 antisense oligonucleotides blocked Fn-induced EP4 expression. Using full-length and mutated EP4 promoter constructs, we found that Fn stimulation of EP4 gene expression was inhibited when one AP-2 site (–1000 bp) was mutated. Fn induced nuclear AP-2 protein expression through multiple signaling pathways. Our results indicate that Fn-induced NSCLC cell proliferation is mediated through EP4. Furthermore, they show that Fn induces EP4 expression through the activation of 51-dependent signals that include induction of extracellular signal-regulated kinase and phosphoinositide 3-kinase pathways as well as expression of COX-2. These events lead to activation of the transcription factor AP-2, which interacts with specific regions in the EP4 gene promoter, leading to transcription of the EP4 gene.

Received for publication, November 3, 2006 , and in revised form, January 4, 2007.

^* This work was supported by American Lung Association Grant RG-10215N (to S. W. H.) and by a Merit Review Grant from the Department of Veterans Affairs (to J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom all correspondence and reprint requests should be addressed: Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Whitehead Bioresearch Bldg., 615 Michael St., Suite 205-M, Atlanta, GA 30322. Tel.: 4047122661; Fax: 4047122151; E-mail: shan2{at}emory.edu.

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