Induction of NAD+-Linked 15-Hydroxyprostaglandin Dehydrogenase Expression by Androgens in Human Prostate Cancer Cells

Abstract

Prostate cancer cells are known to express cyclooxygenases (COXs) and synthesize prostaglandins. Catabolism of prostaglandins in these cells remains to be determined. Induction of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (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 time- and dose-dependent manner in LNCaP but not in PC3 cells as shown by activity assay and immunoblot analysis. However, prostaglandin synthetic enzymes, COX-1 and COX-2, were not found to be induced by androgens. Induction was also achieved by 17β-estradiol and progesterone, although to a lesser extent. Induction of 15-PGDH was not blocked by steroid receptor antagonist, RU 486, nor by antiandrogen, flutamide. However, induction was inhibited by tyrosine kinase inhibitor, genistein, and by ERK kinase inhibitor, PD 98059, but not by protein kinase C inhibitor, GF109203X. These results suggest that androgens induce 15-PGDH gene expression through an unconventional nongenomic pathway.