PROSTAGLANDIN E₂ stimulates cancer-related phenotypes in prostate cancer PC3 cells through cyclooxygenase-2

Cyclooxygenase (COX)-derived prostaglandin E2 (PGE₂ ) affects many mechanisms that have been shown to play roles in carcinogenesis. Recently, we found that, in androgen-independent prostate cancer PC3 cells, PGE₂ acts through an intracrine mechanism by which its uptake by the prostaglandin transporter (PGT) results in increased intracellular PGE₂ (iPGE₂ ), leading to enhanced cell proliferation, migration, invasion, angiogenesis, and loss of cell adhesion to collagen I. These iPGE₂ -mediated effects were dependent on hypoxia-inducible factor 1-α (HIF-1α), whose expression increased upon epidermal growth factor receptor (EGFR) transactivation by a subset of intracellular PGE₂ receptors. Here, we aimed to study the role of COX in PGE₂ protumoral effects in PC3 cells and found that the effects were prevented by inhibition of COX-2, which highlights its crucial role amplifying the levels of iPGE₂ . Treatment with exogenous PGE₂ determined a transcriptional increase in COX-2 expression, which was abolished by genetic or pharmacologic inhibition of PGT. PGE₂ -induced increase in COX-2 expression and, thereby, in transcriptional increase in HIF-1α expression was due to EGFR activation, leading to the activation of Phosphoinositide 3-kinase/Akt, Extracellular signal -regulated kinases 1/2, p38 and Mitogen- and stress-activated protein kinase-1 (PI3K/Akt, Erk1/2, p38 and MSK-1). Collectively, the data suggest that EGFR-dependent COX-2 upregulation by a novel positive feedback loop triggered by iPGE₂ underlies the intracrine pro-tumoral effects of PGE₂ in PC3 cells. Therefore, this feedback loop may be relevant in prostate cancer for the maintenance of PGE₂ -dependent cancer cell growth through amplifying the activity of the COX-2 pathway.