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Submitted on September 22, 2003
Accepted on January 14, 2004
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082
* To whom correspondence should be addressed. E-mail: htai1{at}uky.edu.
NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of 15 (S)-hydroxyl group of prostaglandins and lipoxins and participates along with cyclooxygenases and lipoxygenases in controlling the cellular levels of prostaglandins and lipoxins. 15-PGDH could be induced by IL-6 and forskolin in addition to androgens in a time and dose dependent manner, but not by other cytokines and growth factors in LNCaP cells. Concurrent addition of IL-6 and forskolin showed additive effect in the induction of 15-PGDH activity. However, combined addition of DHT and IL-6 or DHT plus forskolin exhibited synergistic induction of 15-PGDH activity. The increase in enzyme activity was correlated with the expression of the enzyme protein as shown by Western blot analysis. The induction by DHT or IL-6 or forskolin or their combinations was inhibited by anti-androgen, casodex, in a dose dependent manner indicating that a functional androgen receptor was required for the action of any of these three agents. The induction by forskolin plus DHT or by either agent or by IL-6 alone was greatly inhibited by H-89 indicating the involvement of protein kinase A in the actions of forskolin, DHT and IL-6. The induction of 15-PGDH by IL-6 was also blocked by some other protein kinase inhibitors indicating the participation of MAPK, MEK and STAT3 in the signaling pathway of IL-6. These results indicate that the induction of 15-PGDH by DHT, IL-6 and forskolin in LNCaP cells may involve a functional androgen receptor and phosphorylation dependent multiple signaling pathways.
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