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-κB): potential implications on prostate cancer chemoprevention and
| Autor: | Kwok-Ming Yao, Chun W. Tam, Vincent W.S. Liu, Stephen Y. W. Shiu, Wai Y. Leung |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Down-Regulation Biology Melatonin chemistry.chemical_compound Endocrinology Cell Line Tumor LNCaP medicine Humans Protein kinase A Transcription factor Protein kinase C Activator (genetics) Receptor Melatonin MT1 NF-kappa B Prostatic Neoplasms NF-κB Molecular biology Up-Regulation Androgen receptor chemistry Cancer research Cyclin-Dependent Kinase Inhibitor p27 medicine.drug |
| Zdroj: | Journal of Pineal Research. 54:69-79 |
| ISSN: | 0742-3098 |
| DOI: | 10.1111/j.1600-079x.2012.01026.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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