MELATONIN DOWNREGULATES ANDROGEN RECEPTOR ACTIVITY

     Another potentially useful agent for hair loss prevention and/or treatment may be right under our noses. Recent studies out of prostate research have shown melatonin to downregulate androgen and estrogen receptor activity, the activity of which is directly related to hormonal hair loss. Studies in various animal species have shown a dramatic increase in hair and fur production in response to the administration of melatonin.
     
Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells.
Rimler A, Lupowitz Z, Zisapel N.
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University; Tel Aviv 69978 Israel.
OBJECTIVES: The pineal hormone melatonin inhibits the growth of benign human prostate epithelial cells and the androgen-dependent prostate cancer LNCaP cells. In the androgen-nonresponsive prostate carcinoma PC3 cells melatonin inhibits cell growth only at high but not low cell density. We have recently found that melatonin causes nuclear exclusion of the AR and attenuates it transcriptional activity in LNCaP cells as well as PC3 cells stably transfected with a wild type AR expressing vector (PC3-AR). The aim of this study was to investigate whether melatonin inhibits effects of AR on cell growth in PC3-AR cells and whether inhibition of AR DNA binding is involved. METHODS: The effects of androgen, melatonin and their combination on the growth of the PC3-AR cells and on AR DNA binding in PC3-AR and LNCaP cells were studied. RESULTS: DHT suppressed cell growth in the PC3-AR cells and enhanced AR binding to the androgen responsive element (ARE). Melatonin had no effect on cell growth in the absence of DHT but counteracted the androgen-induced inhibition at low androgen concentrations. Melatonin did not suppress and even slightly enhanced the capacity of AR binding to the ARE in the PC3-AR as well as in LNCaP cells. CONCLUSIONS: Attenuation by melatonin of AR activity in the prostate cancer cells is not due to suppression of AR binding to the ARE, and is presumably caused by its effects on AR protein interaction and intracellular trafficking.
     
Melatonin elicits nuclear exclusion of the human androgen receptor and attenuates its activity.
Rimler A, Culig Z, Levy-Rimler G, Lupowitz Z, Klocker H, Matzkin H, Bartsch G, Zisapel N.
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
BACKGROUND: The androgen receptor (AR) promotes growth and functionality of androgen sensitive benign and cancer tissues. The pineal hormone melatonin is an androgen protagonist in vivo and in vitro. The interference of melatonin in the AR cascade was explored. METHODS: The effects of melatonin on AR expression, level, agonist and androgen-response element (ARE) binding, reporter gene activity and intracellular localization were explored in prostate cancer LNCaP cell line. RESULTS: Melatonin increased immunoreactive AR cells in the absence and presence of dihydrotestosterone. Despite this increase and maintenance of AR agonist binding capacity, the androgen-induced reporter gene activity and suppression of AR-mRNA were attenuated.
      Immunocytochemical analysis and subcellular fractionation studies revealed nuclear exclusion of AR by melatonin.
CONCLUSIONS: The melatonin-mediated nuclear exclusion of the AR may explain the attenuation of AR activity in the prostate cancer cells. This is the first demonstration of a hormone-induced mislocalization of the AR in prostate epithelial cells and may represent a novel route for regulating AR activity. Copyright 2001 Wiley-Liss, Inc.
      *The doses used to downregulate androgen receptor activity is very high, and involved the equivilant of 1mg per every kilogram of bodyweight. However the sleep effects of melatonin are not dose dependent, (3mg works as well as 50mg.), and the same possibly apply to androgen receptor activity as well.



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