Melatonin MT1 receptor-induced transcriptional up-regulation of p27Kip1 in prostate cancer antiproliferation is mediated via inhibition of constitutively active nuclear factor kappa B (NF-kB): potential implications on prostate cancer chemoprevention and
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 p27Kip1 through dual activation of Gαs/protein kinase A (PKA) and Gαq/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 p27Kip1 in LNCaP and 22Rv1 prostate cancer cells.
Deletion mapping and reporter assays of the p27Kip1 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-kB) binding site.
When the NF-kB binding site was abolished by site-directed mutagenesis, the stimulatory effect of melatonin on p27Kip1 promoter activity was mitigated.
Notably, melatonin inhibited the DNA binding of activated NF-kB via MT1 receptor-induced PKA and PKC stimulation. Furthermore, melatonin’s up-regulatory effect on p27Kip1 transcription and consequent cell antiproliferation were abrogated by NF-kB activator but mimicked by NF-kB inhibitor.
The results indicate that inhibition of constitutively active NF-kB via melatonin MT1 receptor-induced dual activation of (Gαs) PKA and (Gαq) PKC can de-repress the p27Kip1 promoter leading to transcriptional up-regulation of p27Kip1.
MT1 receptor-mediated inhibition of activated NF-kB signaling provides a novel mechanism supporting the use of melatonin in prostate cancer chemoprevention and therapy.
See also About Melatonin.