title: Evaluation of signal transduction pathways mediating the nuclear exclusion of the androgen receptor by melatonin.
abstract: The intracellular signaling pathways mediating the nuclear exclusion of the androgen receptor (AR) by melatonin were evaluated in PC3 cells stably transfected with the AR. The melatonin-induced nuclear exclusion of the AR by melatonin (100 nM, 3 h) was blocked by LY 83583 (an inhibitor of guanylyl cyclases). 8-Bromo-cGMP (a cell-permeable cGMP analog), mimicked the effect of melatonin, as did ionomycin (a calcium ionophore) and PMA [an activator of protein kinase C (PKC)], and their effects were blocked by GF- 109203X (a selective PKC inhibitor). BAPTA (an intracellular calcium chelator) blocked the effects of melatonin and 8-bromo-cGMP but not of PMA. Inhibition or activation of the protein kinase A pathway did not affect basal or melatonin-mediated AR localization. We conclude that the melatonin-mediated rise in cGMP elicits AR nuclear exclusion via a pathway involving increased intracellular calcium and PKC activation. These results define a novel signaling pathway that regulates AR localization and androgen responses in target cells.
authors.affiliation: Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Lupowitz
authors.forename: A
authors.initials: A
authors.lastname: Rimler
authors.forename: N
authors.initials: N
authors.lastname: Zisapel
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000634:Aminoquinolines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D002614:Chelating Agents; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007476:Ionophores; D011944:Receptors, Androgen; C016276:8-bromocyclic GMP; C041715:6-anilino-5,8-quinolinedione; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D006152:Cyclic GMP; D008550:Melatonin