Evaluation of signal transduction pathways mediating the nuclear exclusion of the androgen receptor by melatonin.
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.
Lupowitz
Z
Z
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
Rimler
A
A
Zisapel
N
N
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
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