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Cyclooxygenase (COX)-derived prostaglandin E2 (PGE 2 ) affects many mechanisms that have been shown to play roles in carcinogenesis. Recently, we found that, in androgenindependent prostate cancer PC3 cells, PGE 2 acts through an intracrine mechanism by which its uptake by the prostaglandin transporter (PGT) results in increased intracellular PGE 2 (iPGE 2 ), leading to enhanced cell proliferation, migration, invasion, angiogenesis, and loss of cell adhesion to collagen I. These iPGE 2 -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 PGE 2 receptors. Here, we aimed to study the role of COX in PGE 2 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 iPGE 2 . Treatment with exogenous PGE 2 determined a transcriptional increase in COX-2 expression, which was abolished by genetic or pharmacologic inhibition of PGT. PGE 2 -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 iPGE 2 underlies the intracrine pro-tumoral effects of PGE 2 in PC3 cells. Therefore, this feedback loop may be relevant in prostate cancer for the maintenance of PGE 2 -dependent cancer cell growth through amplifying the activity of the COX-2 pathway.

Prostaglandin E (PGE ) increases cell proliferation and stimulates migratory and angiogenic abilities in prostate cancer cells. However, the effects of PGE on non-transformed prostate epithelial cells are unknown, despite the fact that PGE overproduction has been found in benign hyperplastic prostates. In the present work we studied the effects of PGE in immortalized, non-malignant prostate epithelial RWPE-1 cells and found that PGE increased cell proliferation, cell migration, and production of vascular endothelial growth factor-A, and activated in vitro angiogenesis. These actions involved a non-canonic intracrine mechanism in which the actual effector was intracellular PGE (iPGE ) instead of extracellular PGE : inhibition of the prostaglandin uptake transporter (PGT) or antagonism of EP receptors prevented the effects of PGE , which indicated that PGE activity depended on its carrier-mediated translocation from the outside to the inside of cells and that EP receptors located intracellularly (iEP) mediated the effects of PGE . iPGE acted through transactivation of epidermal growth factor-receptor (EGFR) by iEP, leading to increased expression and activity of hypoxia-inducible factor-1α (HIF-1α). Interestingly, iPGE also mediates the effects of PGE on prostate cancer PC3 cells through the axis iPGE -iEP receptors-EGFR-HIF-1α. Thus, this axis might be responsible for the growth-stimulating effects of PGE on prostate epithelial cells, thereby contributing to prostate proliferative diseases associated with chronic inflammation. Since this PGT-dependent non-canonic intracrine mechanism of PGE action operates in both benign and malignant prostate epithelial cells, PGT inhibitors should be tested as a novel therapeutic modality to treat prostate proliferative disease.

In Spain, the public health benefits of the Directive 2004/24/EC might be less than expected.

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