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Melatonin MT1 receptor-induced transcriptional up-regulation of p27(Kip1) in prostate cancer antiproliferation is mediated via inhibition of constitutively active nuclear factor kappa B (NF-κB): potential implications on prostate cancer chemoprevention and therapy.

Abstract
Our laboratory has recently demonstrated a melatonin MT1 receptor-mediated antiproliferative signaling mechanism in androgen receptor (AR)-positive prostate epithelial cells which involves up-regulation of p27(Kip1) through dual activation of Gα(s)/protein kinase A (PKA) and Gα(q)/protein kinase C (PKC) in parallel, and down-regulation of activated AR signaling via PKC stimulation. The aim of the present investigation was to identify the transcription factor that mediates melatonin's up-regulatory effect on p27(Kip1) in LNCaP and 22Rv1 prostate cancer cells. Deletion mapping and reporter assays of the p27(Kip1) promoter revealed that the putative melatonin-responsive transcription factor binds to a 116 base-pair region of the promoter sequence, which contains a potential nuclear factor kappa B (NF-κB) binding site. When the NF-κB binding site was abolished by site-directed mutagenesis, the stimulatory effect of melatonin on p27(Kip1) promoter activity was mitigated. Notably, melatonin inhibited the DNA binding of activated NF-κB via MT1 receptor-induced PKA and PKC stimulation. Furthermore, melatonin's up-regulatory effect on p27(Kip1) transcription and consequent cell antiproliferation were abrogated by NF-κB activator but mimicked by NF-κB inhibitor. The results indicate that inhibition of constitutively active NF-κB via melatonin MT1 receptor-induced dual activation of (Gα(s)) PKA and (Gα(q)) PKC can de-repress the p27(Kip1) promoter leading to transcriptional up-regulation of p27(Kip1). MT1 receptor-mediated inhibition of activated NF-κB signaling provides a novel mechanism supporting the use of melatonin in prostate cancer chemoprevention and therapy.
AuthorsStephen Y W Shiu, Wai Y Leung, Chun W Tam, Vincent W S Liu, Kwok-Ming Yao
JournalJournal of pineal research (J Pineal Res) Vol. 54 Issue 1 Pg. 69-79 (Jan 2013) ISSN: 1600-079X [Electronic] England
PMID22856547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2012 John Wiley & Sons A/S.
Chemical References
  • NF-kappa B
  • Receptor, Melatonin, MT1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Melatonin
Topics
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p27 (genetics)
  • Down-Regulation
  • Humans
  • Male
  • Melatonin (pharmacology)
  • NF-kappa B (antagonists & inhibitors)
  • Prostatic Neoplasms (drug therapy, prevention & control)
  • Receptor, Melatonin, MT1 (genetics)
  • Up-Regulation (drug effects)

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