Synergistic induction of the nicotinamide adenine dinucleotide-linked 15-hydroxyprostaglandin dehydrogenase by an androgen and interleukin-6 or forskolin in human prostate cancer cells.
The nicotinamide adenine dinucleotide-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 dihydrotestosterone (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 antiandrogen, 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, MAPK/ERK kinase, 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.
Tong
Min
M
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
Tai
Hsin-Hsiung
HH
D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D015153:Blotting, Western; D005576:Colforsin / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011944:Receptors, Androgen / Q000502:physiology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013449:Sulfonamides; D014105:Tosyl Compounds; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D000813:Anilides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D007546:Isoquinolines; D009570:Nitriles; D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D014105:Tosyl Compounds; D015534:Trans-Activators; D013196:Dihydrotestosterone; D005576:Colforsin; C053541:bicalutamide; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide