Role of intracellular prostaglandin E2 in cancer-related phenotypes in PC3 cells

Prostaglandin E-2 (PGE(2)) and hypoxia-inducible factor-1 alpha (HIF-1 alpha) affect many mechanisms that have been shown to play a role in prostate cancer. In PGE(2)-treated LNCaP cells, up-regulation of HIF-1 alpha requires the internalization of PGE(2), which is in sharp contrast with the generally accepted view that PGE(2) acts through EP receptors located at the cell membrane. Here we aimed to study in androgen-independent PC3 cells the role of intracellular PGE(2) in several events linked to prostate cancer progression. To this end, we used bromocresol green, an inhibitor of prostaglandin uptake that blocked the immediate rise in intracellular immunoreactive PGE(2) following treatment with 16,16-dimethyl-PGE(2). Bromocresol green prevented the stimulatory effect of 16,16-dimethyl-PGE on cell proliferation, adhesion, migration and invasion and on HIF-1 alpha expression and activity, the latter assessed as the HIF-dependent activation of (i) a hypoxia response element-luciferase plasmid construct, (ii) production of angiogenic factor vascular endothelial growth factor-A and (iii) in vitro angiogenesis. The basal phenotype of PC3 cells was also affected by bromocresol green, that substantially lowered expression of HIF-1 alpha, production of vascular endothelial growth factor-A and cell proliferation. These results, and the fact that we found functional intracellular EP receptors in PC3 cells, suggest that PGE(2)-dependent intracrine mechanisms play a role in prostate cancer Therefore, inhibition of the prostaglandin uptake transporter might be a novel therapeutic approach for the treatment of prostate cancer. (C) 2014 Elsevier Ltd. All rights reserved.