Prostaglandin E₂ Stimulates Human Lung Carcinoma Cell Growth through Induction of Integrin-Linked Kinase: The Involvement of EP4 and Sp1

¹Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine; ²Atlanta Veterans Affairs Medical Center, Atlanta, Georgia and ³Department of Obstetrics and Gynecology, West China 2nd University Hospital, Sichuan University, Chengdu, Sichuan Province, China

^* To whom correspondence should be addressed. E-mail: shan2{at}emory.edu.

	Abstract

Cyclooxygenase-2–derived prostaglandin E₂ (PGE₂) stimulates tumor cell growth and progression. However, the mechanisms by which PGE₂ increases tumor growth remain incompletely understood. In studies performed in non–small cell lung carcinoma (NSCLC) cells, we found that PGE₂ stimulates the expression of integrin-linked kinase (ILK). ILK small interfering RNA (siRNA) inhibited the mitogenic effects of PGE₂. In view of its perceived importance, we turned our attention to the mechanisms involved in PGE₂-induced ILK expression and found that this effect was blocked by an antagonist of the PGE₂ receptor subtype EP4 and by EP4 siRNA. Furthermore, we showed that PGE₂ induction of ILK was associated with phosphorylation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt, which were abrogated by ILK siRNA. Transient transfection, gel mobility shift assays, and chromatin immunoprecipitation experiments showed that PGE₂ induced ILK promoter activity and increased Sp1, although it had no effect on nuclear factor-B and AP-2 DNA-binding activity. Blockade of Sp1 abrogated the effect of PGE₂ on expression of ILK and promoter activity and on cell growth. In summary, our observations show that PGE₂ increases NSCLC cell growth through increased ILK expression, which is dependent on EP4 signaling and on induction of Sp1 protein and Sp1 DNA-binding activity in the ILK promoter. These studies suggest a novel molecular mechanism by which PGE₂ stimulates NSCLC cell growth and unveils a new molecular target for the development of therapies against NSCLC. [Cancer Res 2009;69(3):896–904]

Key Words: PGE₂, ILK, EP4, Sp1, human lung carcinoma cells

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