title: 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.
authors.affiliation: Department of Physiology, The University of Hong Kong, Hong Kong, China Department of Biochemistry, The University of Hong Kong, Hong Kong, China Nursing, School of Science and Technology, Open University of Hong Kong, Hong Kong, China.
authors.forename: Stephen Y W
authors.initials: SY
authors.lastname: Shiu
authors.forename: Wai Y
authors.initials: WY
authors.lastname: Leung
authors.forename: Chun W
authors.initials: CW
authors.lastname: Tam
authors.forename: Vincent W S
authors.initials: VW
authors.lastname: Liu
authors.forename: Kwok-Ming
authors.initials: KM
authors.lastname: Yao
mesh_terms: D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D015536:Down-Regulation; D006801:Humans; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000517:prevention & control*; D044122:Receptor, Melatonin, MT1 / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D044122:Receptor, Melatonin, MT1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008550:Melatonin