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.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA