title: Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism.
abstract: BACKGROUND
  Melatonin, the main secretory product of the pineal gland, inhibits the growth of several types of cancer cells. Melatonin limits human prostate cancer cell growth by a mechanism which involves the regulation of androgen receptor function but it is not clear whether other mechanisms may also be involved.
  
  
  METHODS
  Time-course and dose-dependent studies were performed using androgen-dependent (LNCaP) and independent (PC3) prostate cancer cells. Cell number, cell viability, and cell cycle progression were studied. Neuroendocrine differentiation of these cells was evaluated by studying morphological and biochemical markers. Finally, molecular mechanisms including the participation of melatonin membrane receptors, intracellular cAMP levels, and the PKA signal transduction pathway were also analyzed.
  
  
  RESULTS
  Melatonin treatment dramatically reduced the number of prostate cancer cells and stopped cell cycle progression in both LNCaP and PC3 cells. In addition, it induced cellular differentiation as indicated by obvious morphological changes and neuroendocrine biochemical parameters. The role of melatonin in cellular proliferation and differentiation of prostate cancer cells is not mediated by its membrane receptors nor related to PKA activation.
  
  
  CONCLUSIONS
  The treatment of prostate cancer cells with pharmacological concentrations of melatonin influences not only androgen-sensitive but also androgen-insensitive epithelial prostate cancer cells. Cell differentiation promoted by melatonin is not mediated by PKA activation although it increases, in a transitory manner, intracellular cAMP levels. Melatonin markedly influences the proliferative status of prostate cancer cells. These effects should be evaluated thoroughly since melatonin levels are diminished in aged individuals when prostate cancer typically occurs.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sainz
authors.forename: Juan C
authors.initials: JC
authors.lastname: Mayo
authors.forename: Dun-xian
authors.initials: DX
authors.lastname: Tan
authors.forename: Josefa
authors.initials: J
authors.lastname: León
authors.forename: Lucien
authors.initials: L
authors.lastname: Manchester
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
mesh_terms: D000276:Adjuvants, Immunologic / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018278:Carcinoma, Neuroendocrine; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D008297:Male; D008550:Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011471:Prostatic Neoplasms; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D011944:Receptors, Androgen; D013739:Testosterone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D008550:Melatonin