Intracrine prostaglandin E 2 pro‐tumoral actions in prostate epithelial cells originate from non‐canonical pathways

Prostaglandin E 2 (PGE 2 ) increases cell proliferation and stimulates migratory and angiogenic abilities in prostate cancer cells. However, the effects of PGE 2 on non‐transformed prostate epithelial cells are unknown, despite the fact that PGE 2 overproduction has been found in benign hyperplastic prostates. In the present work we studied the effects of PGE 2 in immortalized, non‐malignant prostate epithelial RWPE‐1 cells and found that PGE 2 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 2 (iPGE 2 ) instead of extracellular PGE 2 : inhibition of the prostaglandin uptake transporter (PGT) or antagonism of EP receptors prevented the effects of PGE 2 , which indicated that PGE 2 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 2 . iPGE 2 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 2 also mediates the effects of PGE 2 on prostate cancer PC3 cells through the axis iPGE 2 ‐iEP receptors‐EGFR‐HIF‐1α. Thus, this axis might be responsible for the growth‐stimulating effects of PGE 2 on prostate epithelial cells, thereby contributing to prostate proliferative diseases associated with chronic inflammation. Since this PGT‐dependent non‐canonic intracrine mechanism of PGE 2 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.