Melatonin MT 1 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 MT 1 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 MT 1 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 MT 1 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. MT 1 receptor-mediated inhibition of activated NF-κB signaling provides a novel mechanism supporting the use of melatonin in prostate cancer chemoprevention and therapy. © 2012 John Wiley & Sons A/S.