Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells.
OBJECTIVE
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.
Rimler
Avi
A
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978 Israel.
Lupowitz
Zippora
Z
Zisapel
Nava
N
D000975:Antioxidants / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004586:Electrophoresis; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D011944:Receptors, Androgen; D004247:DNA; D008550:Melatonin; D013936:Thymidine