Induction of cyclo-oxygenase-2 mRNA by prostaglandin E-2 in human prostatic carcinoma cells

Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclo-oxygenases: COX-I (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E-2 (dmPGE(2)) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE(2) to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE(2) concentration. DmPGE(2) also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE(2) regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE(2) concentration, with maximum stimulation seen at 5 mu g ml(-1). The non-steroidal anti-inflammatory drug flurbiprofen (5 mu M), in the presence of exogenous dmPGE(2), inhibited the up-regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE(2) has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE(2), perhaps resulting from changes in local cellular PGE(2) concentrations.