Induction of NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase expression by androgens in human prostate cancer cells

Prostate cancer cells are known to express cyclooxygenases (COXs) and synth esize prostaglandins, Catabolism of prostaglandins in these cells remains t o be determined. Induction of NAD(+)-dependent 15-hydroxy-prostaglandin deh ydrogenase (15-PGDH), a key metabolic inactivation enzyme, was investigated in androgen-sensitive LNCaP cells and in hormone-independent PC3 cells. 15 -PGDH was found to be induced by dihydrotestosterone or testosterone in a t ime- and dose-dependent manner in LNCaP but not in PC3 cells as shown by ac tivity assay and immunoblot analysis. However, prostaglandin synthetic enzy mes, COX-1 and COX-a, were not found to be induced by androgens, Induction was also achieved by 17 beta-estradiol and progesterone, although to a less er extent. Induction of 15-PGDH was not blocked by steroid receptor antagon ist, RU 486, nor by antiandrogen, flutamide. However, induction was inhibit ed by tyrosine kinase inhibitor, genistein, and by ERK kinase inhibitor, PD 98059, but not by protein kinase C inhibitor, GF109203X. These results sug gest that androgens induce 15-PGDH gene expression through an unconventiona l nongenomic pathway. (C) 2000 Academic Press.