Prostaglandin E₂ (PGE₂) stimulates the proliferation of human lung carcinoma cells through activation of ILK: the involvement of PGE₂ receptor subtype EP4

349

Cyclooxygenase-2-derived prostaglandin E₂ (PGE₂) stimulates tumor cell growth and progression. However, the mechanisms by which PGE₂ stimulates tumor growth remain incompletely understood. Here, we show that PGE₂ induces the mRNA and protein expression of integrin-linked kinase (ILK) in non-small cell lung carcinoma (NSCLC) cells (H1838 and H1792), and that ILK siRNA inhibits the mitogenic effects of PGE₂. In view of its perceived importance, we turned our attention to the mechanisms involved in PGE₂-induced ILK and found that this effect was blocked by an antagonist of the PGE₂ receptor subtype EP4 (AH23848) and by EP4 siRNA. Furthermore, we found that PGE₂ induction of ILK was associated with phosphorylation of ERK and activation of the PI3-K/Akt/mTOR-raptor/p70S6K/4E-BP1 pathway. Interestingly, an inhibitor of ERK (PD98059) and of PI3-K (LY294002) abolished PGE₂-stimulated phosphorylation of Akt, but the PI3-K inhibitor had no effect on PGE₂-induced phosphorylation of ERK. Also, while both inhibitors had no effect on PGE₂-induced expression of ILK, they diminished the phosphorylation of mTOR, p70S6K and 4E-BP1. Most importantly, they reduced NSCLC cell growth induced by PGE₂. Together, these studies suggest that PGE₂ stimulates NSCLC cell proliferation via EP4-mediated signals that activate ILK. In turn, ILK stimulates ERK followed by induction of the PI3-K/Akt/mTOR-raptor/p70S6K-4E-BP1 pathway.