Melatonin as a negative mitogenic hormonal regulator of human prostate epithelial cell growth: potential mechanisms and clinical significance.
Circannual variation in the human serum levels of prostate-specific antigen, a growth marker of the prostate gland, has been reported recently. The present study was conducted to investigate the role of the photoperiodic hormone melatonin (MLT) and its membrane receptors in the modulation of human prostate growth. Expression of MT(1) and MT(2) receptors was detected in benign human prostatic epithelial tissues and RWPE-1 cells. MLT and 2-iodomelatonin inhibited RWPE-1 cell proliferation and up-regulated p27(Kip1) gene and protein expression in the cells. The effects of MLT were blocked by the nonselective MT(1)/MT(2) receptor antagonist luzindole, but were not affected by the selective MT(2) receptor antagonist 4-phenyl-2-propionamidotetraline. Of note, the antiproliferative action of MLT on benign prostate epithelial RWPE-1 cells was effected via increased p27(Kip1) gene transcription through MT(1) receptor-mediated activation of protein kinase A (PKA) and protein kinase C (PKC) in parallel, a signaling process which has previously been demonstrated in 22Rv1 prostate cancer cells. Taken together, the demonstration of the MT(1)/PKA+PKC/p27(Kip1) antiproliferative pathway in benign and malignant prostate epithelial cell lines indicated the potential importance of this MLT receptor-mediated signaling mechanism in growth regulation of the human prostate gland in health and disease. Collectively, our data support the hypothesis that MLT may function as a negative mitogenic hormonal regulator of human prostate epithelial cell growth.
Tam
Chun W
CW
Department of Physiology, The University of Hong Kong, Hong Kong, China.
Chan
Kwok W
KW
Liu
Vincent W S
VW
Pang
Bo
B
Yao
Kwok-Ming
KM
Shiu
Stephen Y W
SY
D000704:Analysis of Variance; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D011467:Prostate / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism; D011494:Protein Kinases / Q000032:analysis; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000378:metabolism; D044094:Receptors, Melatonin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
C114459:4-phenyl-2-propionamidotetraline; D006133:Growth Substances; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; C057154:luzindole; D050760:Cyclin-Dependent Kinase Inhibitor p27; C044556:2-iodomelatonin; D011494:Protein Kinases; D008550:Melatonin