Intracrine prostaglandin E₂ pro-tumoral actions in prostate epithelial cells originate from non-canonical pathways

Prostaglandin E₂ (PGE₂ ) increases cell proliferation and stimulates migratory and angiogenic abilities in prostate cancer cells. However, the effects of PGE₂ on non-transformed prostate epithelial cells are unknown, despite the fact that PGE₂ overproduction has been found in benign hyperplastic prostates. In the present work we studied the effects of PGE₂ in immortalized, non-malignant prostate epithelial RWPE-1 cells and found that PGE₂ 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 PGE₂ (iPGE₂ ) instead of extracellular PGE₂ : inhibition of the prostaglandin uptake transporter (PGT) or antagonism of EP receptors prevented the effects of PGE₂ , which indicated that PGE₂ 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 PGE₂ . iPGE₂ 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, iPGE₂ also mediates the effects of PGE₂ on prostate cancer PC3 cells through the axis iPGE₂ -iEP receptors-EGFR-HIF-1α. Thus, this axis might be responsible for the growth-stimulating effects of PGE₂ on prostate epithelial cells, thereby contributing to prostate proliferative diseases associated with chronic inflammation. Since this PGT-dependent non-canonic intracrine mechanism of PGE₂ 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.