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

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.